US10000467B2 - Cyanine compounds - Google Patents
Cyanine compounds Download PDFInfo
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- US10000467B2 US10000467B2 US15/042,328 US201615042328A US10000467B2 US 10000467 B2 US10000467 B2 US 10000467B2 US 201615042328 A US201615042328 A US 201615042328A US 10000467 B2 US10000467 B2 US 10000467B2
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- ANRHNWWPFJCPAZ-UHFFFAOYSA-M thionine Chemical class [Cl-].C1=CC(N)=CC2=[S+]C3=CC(N)=CC=C3N=C21 ANRHNWWPFJCPAZ-UHFFFAOYSA-M 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 671
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- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 claims description 22
- 238000003556 assay Methods 0.000 claims description 18
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- 229960002685 biotin Drugs 0.000 claims description 11
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- 238000011503 in vivo imaging Methods 0.000 claims description 10
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- 229940079593 drug Drugs 0.000 claims description 9
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- 229940088597 hormone Drugs 0.000 claims description 5
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- 239000012472 biological sample Substances 0.000 claims 2
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- 150000001720 carbohydrates Chemical class 0.000 claims 2
- 239000002777 nucleoside Substances 0.000 claims 2
- 229920000620 organic polymer Polymers 0.000 claims 2
- 235000011178 triphosphate Nutrition 0.000 claims 2
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- 229920001223 polyethylene glycol Polymers 0.000 description 508
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 305
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 257
- 229940125904 compound 1 Drugs 0.000 description 244
- 229940125782 compound 2 Drugs 0.000 description 186
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 165
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- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 61
- 125000005392 carboxamide group Chemical group NC(=O)* 0.000 description 56
- 125000004964 sulfoalkyl group Chemical group 0.000 description 51
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 42
- 0 *COCCOCCOCCC(ON(C(CC1)=O)C1=O)=O Chemical compound *COCCOCCOCCC(ON(C(CC1)=O)C1=O)=O 0.000 description 41
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 41
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- 239000012964 benzotriazole Substances 0.000 description 40
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 39
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 36
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- 125000001931 aliphatic group Chemical group 0.000 description 32
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- QGKMIGUHVLGJBR-UHFFFAOYSA-M (4z)-1-(3-methylbutyl)-4-[[1-(3-methylbutyl)quinolin-1-ium-4-yl]methylidene]quinoline;iodide Chemical compound [I-].C12=CC=CC=C2N(CCC(C)C)C=CC1=CC1=CC=[N+](CCC(C)C)C2=CC=CC=C12 QGKMIGUHVLGJBR-UHFFFAOYSA-M 0.000 description 19
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 18
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- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 16
- LIMQGGPXMHPSNS-YLAZTISZSA-K COCCN1=C(/C=C/C=C/C=C/C=C2/N(CCOCCC(=O)ON3C(=O)CCC3=O)C3=C(C=C(S(=O)(=O)[O-])C=C3)C2(C)CCOC)C(C)(CCCS(=O)(=O)[O-])C2=C1C=CC(S(=O)(=O)[O-])=C2 Chemical compound COCCN1=C(/C=C/C=C/C=C/C=C2/N(CCOCCC(=O)ON3C(=O)CCC3=O)C3=C(C=C(S(=O)(=O)[O-])C=C3)C2(C)CCOC)C(C)(CCCS(=O)(=O)[O-])C2=C1C=CC(S(=O)(=O)[O-])=C2 LIMQGGPXMHPSNS-YLAZTISZSA-K 0.000 description 15
- NFAHSUWFVODAIG-SCHSSIMOSA-K COCCN1=C(/C=C/C=C2/N(CCOCCC(=O)ON3C(=O)CCC3=O)C3=C(C=C(S(=O)(=O)[O-])C=C3)C2(C)CCOC)C(C)(CCCS(=O)(=O)[O-])C2=C1C=CC(S(=O)(=O)[O-])=C2 Chemical compound COCCN1=C(/C=C/C=C2/N(CCOCCC(=O)ON3C(=O)CCC3=O)C3=C(C=C(S(=O)(=O)[O-])C=C3)C2(C)CCOC)C(C)(CCCS(=O)(=O)[O-])C2=C1C=CC(S(=O)(=O)[O-])=C2 NFAHSUWFVODAIG-SCHSSIMOSA-K 0.000 description 15
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
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- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical class [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 8
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- KBPLFHHGFOOTCA-UHFFFAOYSA-N caprylic alcohol Natural products CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 8
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- CTRLRINCMYICJO-UHFFFAOYSA-N phenyl azide Chemical compound [N-]=[N+]=NC1=CC=CC=C1 CTRLRINCMYICJO-UHFFFAOYSA-N 0.000 description 1
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
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- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
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- ILLNWRQKWKHXHK-UHFFFAOYSA-K trisodium (2E)-2-[(2E,4E)-5-[1-(5-carboxypentyl)-3-methyl-5-sulfonato-3-(3-sulfonatopropyl)indol-1-ium-2-yl]penta-2,4-dienylidene]-1-(2-methoxyethyl)-3-methyl-3-(3-sulfonatopropyl)indole-5-sulfonate Chemical class [Na+].[Na+].[Na+].[O-]S(=O)(=O)CCCC1(C)C2=CC(S([O-])(=O)=O)=CC=C2N(CCOC)\C1=C\C=C\C=C\C1=[N+](CCCCCC(O)=O)C2=CC=C(S([O-])(=O)=O)C=C2C1(C)CCCS([O-])(=O)=O ILLNWRQKWKHXHK-UHFFFAOYSA-K 0.000 description 1
- YFMJJUUQULNXAC-UHFFFAOYSA-K trisodium (2E)-2-[(E)-3-[1-(5-carboxypentyl)-3-methyl-5-sulfonato-3-(3-sulfonatopropyl)indol-1-ium-2-yl]prop-2-enylidene]-1-(2-methoxyethyl)-3-methyl-3-(3-sulfonatopropyl)indole-5-sulfonate Chemical compound [Na+].[Na+].[Na+].[O-]S(=O)(=O)CCCC1(C)C2=CC(S([O-])(=O)=O)=CC=C2N(CCOC)\C1=C\C=C\C1=[N+](CCCCCC(O)=O)C2=CC=C(S([O-])(=O)=O)C=C2C1(C)CCCS([O-])(=O)=O YFMJJUUQULNXAC-UHFFFAOYSA-K 0.000 description 1
- QNIUIRHTSSLLDD-UHFFFAOYSA-K trisodium (2E)-2-[(E)-3-[1-(5-carboxypentyl)-3-methyl-5-sulfonato-3-(3-sulfonatopropyl)indol-1-ium-2-yl]prop-2-enylidene]-1-[2-(2-methoxyethoxy)ethyl]-3-methyl-3-(3-sulfonatopropyl)indole-5-sulfonate Chemical class [Na+].[Na+].[Na+].[O-]S(=O)(=O)CCCC1(C)C2=CC(S([O-])(=O)=O)=CC=C2N(CCOCCOC)\C1=C\C=C\C1=[N+](CCCCCC(O)=O)C2=CC=C(S([O-])(=O)=O)C=C2C1(C)CCCS([O-])(=O)=O QNIUIRHTSSLLDD-UHFFFAOYSA-K 0.000 description 1
- SOBHUZYZLFQYFK-UHFFFAOYSA-K trisodium;hydroxy-[[phosphonatomethyl(phosphonomethyl)amino]methyl]phosphinate Chemical class [Na+].[Na+].[Na+].OP(O)(=O)CN(CP(O)([O-])=O)CP([O-])([O-])=O SOBHUZYZLFQYFK-UHFFFAOYSA-K 0.000 description 1
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Images
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6871—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting an enzyme
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- A61K49/221—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by the targeting agent or modifying agent linked to the acoustically-active agent
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/08—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing alicyclic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/40—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against enzymes
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
- C09B23/00—Methine or polymethine dyes, e.g. cyanine dyes
- C09B23/0008—Methine or polymethine dyes, e.g. cyanine dyes substituted on the polymethine chain
- C09B23/0016—Methine or polymethine dyes, e.g. cyanine dyes substituted on the polymethine chain the substituent being a halogen atom
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
- C09B23/00—Methine or polymethine dyes, e.g. cyanine dyes
- C09B23/0008—Methine or polymethine dyes, e.g. cyanine dyes substituted on the polymethine chain
- C09B23/0025—Methine or polymethine dyes, e.g. cyanine dyes substituted on the polymethine chain the substituent being bound through an oxygen atom
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
- C09B23/00—Methine or polymethine dyes, e.g. cyanine dyes
- C09B23/0066—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain being part of a carbocyclic ring,(e.g. benzene, naphtalene, cyclohexene, cyclobutenene-quadratic acid)
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
- C09B23/00—Methine or polymethine dyes, e.g. cyanine dyes
- C09B23/02—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups
- C09B23/06—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups three >CH- groups, e.g. carbocyanines
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
- C09B23/00—Methine or polymethine dyes, e.g. cyanine dyes
- C09B23/02—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups
- C09B23/08—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups more than three >CH- groups, e.g. polycarbocyanines
- C09B23/083—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups more than three >CH- groups, e.g. polycarbocyanines five >CH- groups
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- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
- C09B23/00—Methine or polymethine dyes, e.g. cyanine dyes
- C09B23/02—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups
- C09B23/08—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups more than three >CH- groups, e.g. polycarbocyanines
- C09B23/086—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups more than three >CH- groups, e.g. polycarbocyanines more than five >CH- groups
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- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
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- C09B69/00—Dyes not provided for by a single group of this subclass
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- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
- C09B69/00—Dyes not provided for by a single group of this subclass
- C09B69/10—Polymeric dyes; Reaction products of dyes with monomers or with macromolecular compounds
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/58—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances
- G01N33/582—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances with fluorescent label
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
Definitions
- the compounds can be conjugated to proteins and nucleic acids for biological imaging and analysis. Synthesis of the compounds, formation and use of the conjugated compounds, and specific non-limiting examples of each are disclosed.
- Biomolecules e.g., antigens, antibodies, DNA-segments with the corresponding complimentary species for measuring enzyme kinetics, receptor-ligand interactions, nucleic acid hybridization kinetics in vitro as well as in vivo, etc.
- labels or dyes are useful for, e.g., pharmacological characterization of receptors and drugs, binding data, etc.
- Compounds such as xanthylium salts (U.S. Pat. No. 5,846,737) and/or cyanines (U.S. Pat. No. 5,627,027) are used for such applications, but aggregate and form dimers, especially in aqueous solution, due to planarity of their ⁇ -system.
- Compounds that have insufficient hydrophilicity undergo non-specific interactions with various surfaces, resulting in problems when attempting purify the corresponding conjugate, and an unsatisfactory signal to noise ratio.
- Efforts are directed to reducing undesirable properties by introducing substituents that increase the hydrophilicity of the compounds.
- substituents that increase the hydrophilicity of the compounds.
- sulfonic acid function substituents have been introduced into the cyanine chromophore.
- U.S. Pat. No. 6,083,485 (Licha) and U.S. Pat. Nos. 6,977,305 and 6,974,873 (Molecular Probes) disclose cyanine compounds having one of the common methyl groups in the 3-position of the terminal indole heterocycle substituted by a ⁇ -carboxyalkyl function, and in which the previously present (e.g.
- N-alkyl or N- ⁇ -carboxyalkyl functions are replaced by N-w-alkyl sulfonic acid functions.
- WO 05/044923 discloses cyanine compounds having the common methyl substituent in the 3-position of the terminal indole heterocycle substituted by a N- ⁇ -alkyl sulfonic acid function.
- cyanine compounds having more than two sulfonic acid function substituents exhibited higher solubility and correspondingly a lower tendency to dimer formation, in comparison to cyanine compounds (Cy3, Cy5) described in U.S. Pat. No. 5,627,027.
- the disclosed cyanine compounds are useful as labels in optical, especially fluorescence optical, determination and detection methods.
- the compounds have high hydrophilicity, high molar absorbance, high photo-stability, and high storage stability. These compounds can be excited by monochromatic (e.g., lasers, laser diodes) or polychromatic (e.g., white light sources) light in the ultraviolet (UV), visible, and near infrared (NIR) spectral region to generate emission of fluorescence light.
- monochromatic e.g., lasers, laser diodes
- polychromatic e.g., white light sources
- Typical application methods are based on the reaction of the compounds with biomolecules such as proteins (e.g., antigens, antibodies, etc.), DNA and/or RNA segments, etc. with the corresponding complimentary species.
- biomolecules such as proteins (e.g., antigens, antibodies, etc.), DNA and/or RNA segments, etc. with the corresponding complimentary species.
- the compounds are useful to measure enzyme kinetics, receptor-ligand interactions, and nucleic acid hybridization kinetics in vitro and/or in vivo.
- the compounds are useful for the pharmacological characterization of receptors and/or drugs.
- Applications include, but are not limited to, uses in medicine, pharmacy, biological sciences, materials sciences, environmental control, detection of organic and inorganic micro samples occurring in nature, etc.
- 1 is ethylene glycol (PEG 1 ) on an indole N
- 2 is diethylene glycol (PEG 2 ) on an indole N
- X is the total number of PEG groups on the compound.
- 650 Compound 4/4 contains PEG 4 on an indole N and a total of four PEG groups on the compound.
- the cyanine compounds have, in an N-position of one heterocycle, ethylene glycol, diethylene glycol, or an ethylene glycol polymer (i.e., poly(ethylene) glycol, abbreviated as PEG), and the other heterocycle has, in a N-position, a function for conjugating the compound to a biomolecule, and an ethylene glycol, diethylene glycol, or an ethylene glycol polymer (i.e., poly(ethylene) glycol, abbreviated as PEG) in another position of the cyanine compound.
- the cyanine compound has, in any position of the compound, at least one sulfo and/or sulfoalkyl.
- the cyanine compound has, in any position of the compound, a sulfonamide and/or carboxamide comprising an ethylene glycol group or an ethylene glycol polymer (i.e., poly(ethylene) glycol, abbreviated as PEG), either directly or indirectly attached to the compound.
- a sulfonamide and/or carboxamide comprising an ethylene glycol group or an ethylene glycol polymer (i.e., poly(ethylene) glycol, abbreviated as PEG), either directly or indirectly attached to the compound.
- PEG poly(ethylene) glycol
- the cyanine compounds have, in an N-position of one heterocycle, an ethylene glycol, diethylene glycol, or ethylene glycol polymer (i.e., poly(ethylene) glycol, abbreviated as PEG), and the other heterocycle has, in a N-position, an ethylene glycol, diethylene glycol, or ethylene glycol polymer (i.e., poly(ethylene) glycol, abbreviated as PEG) and a function for conjugating the compound to a biomolecule, and an ethylene glycol group or an ethylene glycol polymer (i.e., poly(ethylene) glycol, abbreviated as PEG) in another position of the benzocyanine compound.
- PEG poly(ethylene) glycol, abbreviated as PEG
- the cyanine compound has, in any position of the compound, at least one sulfo and/or sulfoalkyl. In one embodiment, the cyanine compound has, in any position of the compound, a sulfonamide and/or carboxamide comprising an ethylene glycol, diethylene glycol, or ethylene glycol polymer (i.e., poly(ethylene) glycol, abbreviated as PEG), either directly or indirectly attached to the compound. Indirect attachment indicates use of a linker, direct attachment indicates lack of such a linker.
- a linker can be any moiety.
- FIGS. 1A-C show the absorption maxima for compounds and conjugated compounds.
- FIG. 2 shows fluorescence plate functional assay results with inventive compounds and commercial dyes in one embodiment.
- FIG. 3 shows fluorescence plate functional assay results with inventive compounds and commercial dyes in one embodiment.
- FIG. 4 shows fluorescence plate functional assay results with inventive compounds and commercial dyes in one embodiment.
- FIG. 5 shows fluorescence plate functional assay results with inventive compounds and commercial dyes in one embodiment.
- FIG. 6 shows fluorescence plate functional assay results with inventive compounds and commercial dyes in one embodiment.
- FIG. 7 shows fluorescence plate functional assay results with inventive compounds and commercial dyes in one embodiment.
- FIG. 8 shows fluorescence plate functional assay results with inventive compounds and commercial dyes in one embodiment.
- FIG. 9 shows fluorescence plate functional assay results with inventive compounds and commercial dyes in one embodiment.
- FIGS. 10A-B show the average total unbound fluorescence intensity with inventive compounds and commercial dyes in one embodiment.
- FIGS. 11A-B show the average total unbound fluorescence intensity with inventive compounds and commercial dyes in one embodiment.
- FIGS. 12A-B show the average total unbound fluorescence intensity with inventive compounds and commercial dyes in one embodiment.
- FIGS. 13A-B show the average total unbound fluorescence intensity with inventive compounds and commercial dyes in one embodiment.
- FIGS. 14A-E show immunofluorescence assay results with inventive compounds and commercial dyes in one embodiment.
- FIG. 15 shows the immunofluorescence assay results of FIG. 14 expressed as fluorescence intensity.
- FIG. 16 shows the immunofluorescence assay results of FIG. 14 expressed as signal-to-background ratio.
- FIGS. 17A-D show immunofluorescence assay results with inventive compounds and commercial dyes in one embodiment.
- FIG. 18 shows the immunofluorescence assay results of FIG. 17 expressed as fluorescence intensity.
- FIG. 19 shows the immunofluorescence assay results of FIG. 17 expressed as signal-to-background ratio.
- FIGS. 20A-D show immunofluorescence assay results with inventive compounds and commercial dyes in one embodiment.
- FIG. 21 shows the immunofluorescence assay results of FIG. 20 expressed as fluorescence intensity.
- FIG. 22 shows the immunofluorescence assay results of FIG. 20 expressed as signal-to-background ratio.
- the compound is a compound according to general formula Ia with “a” indicating the chain from the right indole N terminates in COX:
- the PEG group is selected from —C—C—O—C (ethylene glycol with terminal methyl), —C—C—O—C—C—O—C (diethylene glycol with terminal methyl), —C—C—O—C—C—O—C—C—O—C ((poly)ethylene glycol (3) with terminal methyl), —C—C—O—C—C—O—C—C—O—C ((poly)ethylene glycol (4) with terminal methyl), —C—C—O—C—C—O—C—C—O—C—C—O—C((poly)ethylene glycol (5) with terminal methyl), or C—C—O—C—C—O—C—C—O—C—C—C—O—C—C—O—C((poly)ethylene glycol (6) with terminal methyl).
- the PEG group P may be either uncapped, e.g., lack a terminal methyl, or may be capped with an atom or group other than a methyl.
- the PEG group P terminates with a Z group, where Z is selected from H, CH 3 , a CH 3 group, alkyl, or a heteroalkyl group.
- the compound is general formula I where R1 is sulfoalkyl and R2 is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 0; o is 3; and n is 1.
- the compound is general formula I where R1 is sulfoalkyl and R2 is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 1; o is 3; and n is 1.
- the compound is general formula I where R1 is sulfoalkyl and R2 is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 2; o is 3; and n is 1.
- the compound is general formula I where R1 is sulfoalkyl and R2 is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 3; o is 3; and n is 1.
- the compound is general formula I where R1 is sulfoalkyl and R2 is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 4; o is 3; and n is 1.
- the compound is general formula I, where R1 is sulfoalkyl and R2 is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 5; o is 3; and n is 1.
- the compound is general formula I where R1 is sulfoalkyl and R2 is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 0; o is 3; and n is 2.
- the compound is general formula I where R1 is sulfoalkyl and R2 is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 1; o is 3; and n is 2.
- the compound is general formula I, where R1 is sulfoalkyl and R2 is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 2; o is 3; and n is 2.
- the compound is general formula I where R1 is sulfoalkyl and R2 is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 3; o is 3; and n is 2.
- the compound is general formula I where R1 is sulfoalkyl and R2 is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 4; o is 3; and n is 2.
- the compound is general formula I where R1 is sulfoalkyl and R2 is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 5; o is 3; and n is 2.
- the compound is general formula I where R1 is sulfoalkyl and R2 is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 0; o is 3; and n is 3.
- the compound is general formula I where R1 is sulfoalkyl and R2 is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 1; o is 3; and n is 3.
- the compound is general formula I where R1 is sulfoalkyl and R2 is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 2; o is 3; and n is 3.
- the compound is general formula I where R1 is sulfoalkyl and R2 is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 3; o is 3; and n is 3.
- the compound is general formula I, where R1 is sulfoalkyl and R2 is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 4; o is 3; and n is 3.
- the compound is general formula I where R1 is sulfoalkyl and R2 is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 5; o is 3; and n is 3.
- the compound is general formula I where R1 is methyl and R2 is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 0; o is 3; and n is 1.
- the compound is general formula I where R1 is methyl and R2 is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 1; o is 3; and n is 1.
- the compound is general formula I where R1 is methyl and R2 is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 2; o is 3; and n is 1.
- the compound is general formula I where R1 is methyl and R2 is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 3; o is 3; and n is 1.
- the compound is general formula I, where R1 is methyl and R2 is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 4; o is 3; and n is 1.
- the compound is general formula I where R1 is methyl and R2 is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 5; o is 3; and n is 1.
- the compound is general formula I where R1 is methyl and R2 is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 0; o is 3; and n is 2.
- the compound is general formula I where R1 is methyl and R2 is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 1; o is 3; and n is 2.
- the compound is general formula I where R1 is methyl and R2 is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 2; o is 3; and n is 2.
- the compound is general formula I where R1 is methyl and R2 is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 3; o is 3; and n is 2.
- the compound is general formula I where R1 is methyl and R2 is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 4; o is 3; and n is 2. In one embodiment the compound is general formula I where R1 is methyl and R2 is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 5; o is 3; and n is 2.
- the compound is general formula I where R1 is methyl and R2 is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 0; o is 3; and n is 3.
- the compound is general formula I where R1 is methyl and R2 is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 1; o is 3; and n is 3.
- the compound is general formula I where R1 is methyl and R2 is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 2; o is 3; and n is 3.
- the compound is general formula I where R1 is methyl and R2 is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 3; o is 3; and n is 3.
- the compound is general formula I where R1 is methyl and R2 is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 4; o is 3; and n is 3.
- the compound is general formula I where R1 is methyl and R2 is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 5; o is 3; n is 3.
- the compound is general formula I where R1 and R2 are PEG groups; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 0; o is 3; and n is 1.
- the compound is general formula I where R1 and R2 are PEG groups; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 1; o is 3; and n is 1.
- the compound is general formula I where R1 and R2 are PEG groups; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 2; o is 3; and n is 1. In one embodiment the compound is general formula I where R1 and R2 are PEG groups; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 3; o is 3; and n is 1.
- the compound is general formula I, where R1 and R2 are PEG groups; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 4; o is 3; and n is 1.
- the compound is general formula I where R1 and R2 are PEG groups; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 5; o is 3; and n is 1.
- the compound is general formula I where R1 and R2 are PEG groups; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 0; o is 3; and n is 2. In one embodiment the compound is general formula I where R1 and R2 are PEG groups; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 1; o is 3; and n is 2.
- the compound is general formula I where R1 and R2 are PEG groups; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 2; o is 3; and n is 2. In one embodiment the compound is general formula I where R1 and R2 are PEG groups; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 3; o is 3; and n is 2.
- the compound is general formula I where R1 and R2 are PEG groups; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 4; o is 3; and n is 2. In one embodiment the compound is general formula I where R1 and R2 are PEG groups; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 5; o is 3; and n is 2.
- the compound is general formula I where R1 and R2 are PEG groups; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 0; o is 3; and n is 3.
- the compound is general formula I where R1 and R2 are PEG groups; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 1; o is 3; and n is 3.
- the compound is general formula I where R1 and R2 are PEG groups; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 2; o is 3; and n is 3.
- the compound is general formula I where R1 and R2 are PEG groups; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 3; o is 3; and n is 3.
- the compound is general formula I, where R1 and R2 are PEG groups; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 4; o is 3; and n is 3.
- the compound is general formula I where R1 and R2 are PEG groups; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 5; o is 3; and n is 3.
- the compound is general formula I where R1 is sulfoalkyl and R2 is a sulfonamide group -L-SO 2 NH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 0; o is 3; and n is 1.
- the compound is general formula I where R1 is sulfoalkyl and R2 is a sulfonamide group -L-SO 2 NH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 1; o is 3; and n is 1.
- the compound is general formula I where R1 is sulfoalkyl and R2 is a sulfonamide group -L-SO 2 NH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 2; o is 3; and n is 1.
- the compound is general formula I where R1 is sulfoalkyl and R2 is a sulfonamide group -L-SO 2 NH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 3; o is 3; and n is 1.
- the compound is general formula I, where R1 is sulfoalkyl and R2 is a sulfonamide group -L-SO 2 NH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 4; o is 3; and n is 1.
- the compound is general formula I where R1 is sulfoalkyl and R2 is a sulfonamide group -L-SO 2 NH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 5; o is 3; and n is 1.
- the compound is general formula I where R1 is sulfoalkyl and R2 is a sulfonamide group -L-SO 2 NH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 0; o is 3; and n is 2.
- the compound is general formula I where R1 is sulfoalkyl and R2 is a sulfonamide group -L-SO 2 NH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 1; o is 3; and n is 2.
- the compound is general formula I where R1 is sulfoalkyl and R2 is a sulfonamide group -L-SO 2 NH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 2; o is 3; and n is 2.
- the compound is general formula I where R1 is sulfoalkyl and R2 is a sulfonamide group -L-SO 2 NH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 3; o is 3; and n is 2.
- the compound is general formula I where R1 is sulfoalkyl and R2 is a sulfonamide group -L-SO 2 NH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 4; o is 3; and n is 2.
- the compound is general formula I where R1 is sulfoalkyl and R2 is a sulfonamide group -L-SO 2 NH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 5; o is 3; and n is 2.
- the compound is general formula I where R1 is sulfoalkyl and R2 is a sulfonamide group -L-SO 2 NH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 0; o is 3; and n is 3.
- the compound is general formula I where R1 is sulfoalkyl and R2 is a sulfonamide group -L-SO 2 NH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 1; o is 3; and n is 3.
- the compound is general formula I where R1 is sulfoalkyl and R2 is a sulfonamide group -L-SO 2 NH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 2; o is 3; and n is 3.
- the compound is general formula I where R1 is sulfoalkyl and R2 is a sulfonamide group -L-SO 2 NH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 3; o is 3; and n is 3.
- the compound is general formula I, where R1 is sulfoalkyl and R2 is a sulfonamide group -L-SO 2 NH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 4; o is 3; and n is 3.
- the compound is general formula I where R1 is sulfoalkyl and R2 is a sulfonamide group -L-SO 2 NH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 5; o is 3; and n is 3.
- an isolated enantiomeric mixture selected from diastereomer Ia of general formula Ia shown below:
- the compound has general formula IIa with “a” indicating the chain from the right indole N terminates in COX:
- each of R 1 , R 2 , R 5 , and R 6 is the same or different and is independently selected from the group consisting of aliphatic, heteroaliphatic, sulfoalkyl, heteroaliphatic with terminal SO 3 , a PEG group P-L-Z where P is selected from an ethylene glycol group, a diethylene glycol group, and a (poly)ethylene glycol group where the (poly)ethylene glycol group is (CH 2 CH 2 O) s where s is an integer from 3-6 inclusive, a sulfonamide group -L-SO 2 NH—P-L-Z, and a carboxamide group -L-CONH—P-L-Z; each of R 7 and R 8 is the same or different and is independently selected from the group consisting of H, SO 3 , a PEG group P-L-Z where P is selected from an ethylene glycol group, a diethylene glycol group, and a (poly)ethylene glycol group where the (poly)ethylene glyco
- the compound is general formula II where R1, R5, and R6 are methyl and R2 is a PEG group; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 0; o is 3; and n is 1.
- the compound is general formula II where R1, R5, and R6 are methyl and R2 is a PEG group; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 1; o is 3; and n is 1.
- the compound is general formula II where R1, R5, and R6 are methyl and R2 is a PEG group; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 2; o is 3; and n is 1.
- the compound is general formula II where R1, R5, and R6 are methyl and R2 is a PEG group; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 3; o is 3; and n is 1.
- the compound is general formula II where R1, R5, and R6 are methyl and R2 is a PEG group; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 4; o is 3; and n is 1.
- the compound is general formula II where R1, R5, and R6 are methyl and R2 is a PEG group; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 5; o is 3; and n is 1.
- the compound is general formula II where R1, R5, and R6 are methyl and R2 is a PEG group; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 0; o is 3; and n is 2.
- the compound is general formula II where R1, R5, and R6 are methyl and R2 is a PEG group; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 1; o is 3; and n is 2.
- the compound is general formula II where R1, R5, and R6 are methyl and R2 is a PEG group; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 2; o is 3; and n is 2.
- the compound is general formula II where R1, R5, and R6 are methyl and R2 is a PEG group; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 3; o is 3; and n is 2.
- the compound is general formula II where R1, R5, and R6 are methyl and R2 is a PEG group; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 4; o is 3; and n is 2.
- the compound is general formula II where R1, R5, and R6 are methyl and R2 is a PEG group; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 5; o is 3; and n is 2.
- the compound is general formula II where R1, R5, and R6 are methyl and R2 is a PEG group; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 0; o is 3; and n is 3.
- the compound is general formula II where R1, R5, and R6 are methyl and R2 is a PEG group; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 1; o is 3; and n is 3.
- the compound is general formula II where R1, R5, and R6 are methyl and R2 is a PEG group; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 2; o is 3; and n is 3.
- the compound is general formula II where R1, R5, and R6 are methyl and R2 is a PEG group; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 3; o is 3; and n is 3.
- the compound is general formula II where R1, R5, and R6 are methyl and R2 is a PEG group; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 4; o is 3; and n is 3.
- the compound is general formula II where R1, R5, and R6 are methyl and R2 is a PEG group; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 5; o is 3; and n is 3.
- the compound is general formula II where R5 and R6 are methyl; R1 and R2 are PEG groups; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 0; o is 3; and n is 1.
- the compound is general formula II where R5 and R6 are methyl; R1 and R2 are PEG groups; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 1; o is 3; and n is 1.
- the compound is general formula II where R5 and R6 are methyl; R1 and R2 are PEG groups; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 2; o is 3; and n is 1.
- the compound is general formula II where R5 and R6 are methyl; R1 and R2 are PEG groups; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 3; o is 3; and n is 1.
- the compound is general formula II, where R5 and R6 are methyl; R1 and R2 are PEG groups; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 4; o is 3; and n is 1.
- the compound is general formula II where R5 and R6 are methyl; R1 and R2 are PEG groups; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 5; o is 3; and n is 1.
- the compound is general formula II where R5 and R6 are methyl; R1 and R2 are PEG groups; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 0; o is 3; and n is 2.
- the compound is general formula II where R5 and R6 are methyl; R1 and R2 are PEG groups; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 1; o is 3; and n is 2.
- the compound is general formula II, where R5 and R6 are methyl; R1 and R2 are PEG groups; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 2; o is 3; and n is 2.
- the compound is general formula II, where R5 and R6 are methyl; R1 and R2 are PEG groups; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 3; o is 3; and n is 2.
- the compound is general formula II, where R5 and R6 are methyl; R1 and R2 are PEG groups; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 4; o is 3; and n is 2.
- the compound is general formula II, where R5 and R6 are methyl; R1 and R2 are PEG groups; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 5; o is 3; and n is 2.
- the compound is general formula II where R5 and R6 are methyl; R1 and R2 are PEG groups; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 0; o is 3; and n is 3.
- the compound is general formula II where R5 and R6 are methyl; R1 and R2 are PEG groups; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 1; o is 3; and n is 3.
- the compound is general formula II where R5 and R6 are methyl; R1 and R2 are PEG groups; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 2; o is 3; and n is 3.
- the compound is general formula II where R5 and R6 are methyl; R1 and R2 are PEG groups; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 3; o is 3; and n is 3.
- the compound is general formula II, where R5 and R6 are methyl; R1 and R2 are PEG groups; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 4; o is 3; and n is 3.
- the compound is general formula II where R5 and R6 are methyl; R1 and R2 are PEG groups; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 5; o is 3; and n is 3.
- the compound is general formula II, where R5 and R6 are methyl; R1 and R2 are PEG groups; R7 is sulfo; R8 is sulfonamide -L-SO 2 NH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 0; o is 3; and n is 1.
- the compound is general formula II, where R5 and R6 are methyl; R1 and R2 are PEG groups; R7 is sulfo; R8 is sulfonamide -L-SO 2 NH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 1; o is 3; and n is 1.
- the compound is general formula II, where R5 and R6 are methyl; R1 and R2 are PEG groups; R7 is sulfo; R8 is sulfonamide -L-SO 2 NH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 2; o is 3; and n is 1.
- the compound is general formula II, where R5 and R6 are methyl; R1 and R2 are PEG groups; R7 is sulfo; R8 is sulfonamide -L-SO 2 NH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 3; o is 3; and n is 1.
- the compound is general formula II, where R5 and R6 are methyl; R1 and R2 are PEG groups; R7 is sulfo; R8 is sulfonamide -L-SO 2 NH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 4; o is 3; and n is 1.
- the compound is general formula II, where R5 and R6 are methyl; R1 and R2 are PEG groups; R7 is sulfo; R8 is sulfonamide -L-SO 2 NH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 5; o is 3; and n is 1.
- the compound is general formula II, where R5 and R6 are methyl; R1 and R2 are PEG groups; R7 is sulfo; R8 is sulfonamide -L-SO 2 NH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 0; o is 3; and n is 2.
- the compound is general formula II, where R5 and R6 are methyl; R1 and R2 are PEG groups; R7 is sulfo; R8 is sulfonamide -L-SO 2 NH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 1; o is 3; and n is 2.
- the compound is general formula II, where R5 and R6 are methyl; R1 and R2 are PEG groups; R7 is sulfo; R8 is sulfonamide -L-SO 2 NH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 2; o is 3; and n is 2.
- the compound is general formula II, where R5 and R6 are methyl; R1 and R2 are PEG groups; R7 is sulfo; R8 is sulfonamide -L-SO 2 NH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 3; o is 3; and n is 2.
- the compound is general formula II, where R5 and R6 are methyl; R1 and R2 are PEG groups; R7 is sulfo; R8 is sulfonamide -L-SO 2 NH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 4; o is 3; and n is 2.
- the compound is general formula II, where R5 and R6 are methyl; R1 and R2 are PEG groups; R7 is sulfo; R8 is sulfonamide -L-SO 2 NH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 5; o is 3; and n is 2.
- the compound is general formula II, where R5 and R6 are methyl; R1 and R2 are PEG groups; R7 is sulfo; R8 is sulfonamide -L-SO 2 NH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 0; o is 3; and n is 3.
- the compound is general formula II, where R5 and R6 are methyl; R1 and R2 are PEG groups; R7 is sulfo; R8 is sulfonamide -L-SO 2 NH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 1; o is 3; and n is 3.
- the compound is general formula II, where R5 and R6 are methyl; R1 and R2 are PEG groups; R7 is sulfo; R8 is sulfonamide -L-SO 2 NH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 2; o is 3; and n is 3.
- the compound is general formula II, where R5 and R6 are methyl; R1 and R2 are PEG groups; R7 is sulfo; R8 is sulfonamide -L-SO 2 NH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 3; o is 3; and n is 3.
- the compound is general formula II, where R5 and R6 are methyl; R1 and R2 are PEG groups; R7 is sulfo; R8 is sulfonamide -L-SO 2 NH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 4; o is 3; and n is 3.
- the compound is general formula II, where R5 and R6 are methyl; R1 and R2 are PEG groups; R7 is sulfo; R8 is sulfonamide -L-SO 2 NH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 5; o is 3; and n is 3.
- the compound is general formula II, where R5 and R6 are methyl; R1 and R2 are PEG groups; R7 is sulfo; R8 is a carboxamide group —CONH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 0; o is 3; and n is 1.
- the compound is general formula II, where R5 and R6 are methyl; R1 and R2 are PEG groups; R7 is sulfo; R8 is a carboxamide group —CONH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 1; o is 3; and n is 1.
- the compound is general formula II, where R5 and R6 are methyl; R1 and R2 are PEG groups; R7 is sulfo; R8 is a carboxamide group —CONH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 2; o is 3; and n is 1.
- the compound is general formula II, where R5 and R6 are methyl; R1 and R2 are PEG groups; R7 is sulfo; R8 is a carboxamide group —CONH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 3; o is 3; and n is 1.
- the compound is general formula II, where R5 and R6 are methyl; R1 and R2 are PEG groups; R7 is sulfo; R8 is carboxamide —CONH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 4; o is 3; and n is 1.
- the compound is general formula II, where R5 and R6 are methyl; R1 and R2 are PEG groups; R7 is sulfo; R8 is a carboxamide group —CONH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 5; o is 3; and n is 1.
- the compound is general formula II, where R5 and R6 are methyl; R1 and R2 are PEG groups; R7 is sulfo; R8 is a carboxamide group —CONH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 0; o is 3; and n is 2.
- the compound is general formula II, where R5 and R6 are methyl; R1 and R2 are PEG groups; R7 is sulfo; R8 is a carboxamide —CONH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 1; o is 3; and n is 2.
- the compound is general formula II, where R5 and R6 are methyl; R1 and R2 are PEG groups; R7 is sulfo; R8 is carboxamide —CONH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 2; o is 3; and n is 2.
- the compound is general formula II, where R5 and R6 are methyl; R1 and R2 are PEG groups; R7 is sulfo; R8 is carboxamide —CONH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 3; o is 3; and n is 2.
- the compound is general formula II, where R5 and R6 are methyl; R1 and R2 are PEG groups; R7 is sulfo; R8 is carboxamide —CONH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 4; o is 3; and n is 2.
- the compound is general formula II, where R5 and R6 are methyl; R1 and R2 are PEG groups; R7 is sulfo; R8 is a carboxamide group —CONH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 5; o is 3; and n is 2.
- the compound is general formula II, where R5 and R6 are methyl; R1 and R2 are PEG groups; R7 is sulfo; R8 is a carboxamide group —CONH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 0; o is 3; and n is 3.
- the compound is general formula II, where R5 and R6 are methyl; R1 and R2 are PEG groups; R7 is sulfo; R8 is a carboxamide group —CONH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 1; o is 3; and n is 3.
- the compound is general formula II, where R5 and R6 are methyl; R1 and R2 are PEG groups; R7 is sulfo; R8 is carboxamide —CONH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 2; o is 3; and n is 3.
- the compound is general formula II, where R5 and R6 are methyl; R1 and R2 are PEG groups; R7 is sulfo; R8 is carboxamide —CONH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 3; o is 3; and n is 3.
- the compound is general formula II, where R5 and R6 are methyl; R1 and R2 are PEG groups; R7 is sulfo; R8 is carboxamide —CONH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 4; o is 3; and n is 3.
- the compound is general formula II, where R5 and R6 are methyl; R1 and R2 are PEG groups; R7 is sulfo; R8 is a carboxamide group —CONH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 5; o is 3; and n is 3.
- the compound has general formula IIIa with “a” indicating the chain from the right indole N terminates in COX:
- each of R 1 , R2, R 5 , and R 6 is the same or different and is independently selected from the group consisting of an aliphatic, heteroaliphatic, sulfoalkyl group, heteroaliphatic with terminal SO 3 , a PEG group P-L-Z where P is selected from an ethylene glycol group, a diethylene glycol group, and a (poly)ethylene glycol group where the (poly)ethylene glycol group is (CH 2 CH 2 O) s where s is an integer from 3-6 inclusive, a sulfonamide group -L-SO 2 NH—P-L-Z, and a carboxamide group -L-CONH—P-L-Z; each of R 7 and R 8 is the same or different and is independently selected from the group consisting of H, SO 3 , a PEG group P-L-Z where P is selected from an ethylene glycol group, a diethylene glycol group, and a (poly)ethylene glycol group where the (poly)ethylene glyco
- the compound is general formula III, where R1, R5, and R6 are methyl; R2 is a PEG group; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 0; p is 1; and n is 1.
- the compound is general formula III, where R1, R5, and R6 are methyl; R2 is a PEG group; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 1; p is 2; and n is 1.
- the compound is general formula III, where R1, R5, and R6 are methyl; R2 is a PEG group; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 2; p is 3; and n is 1.
- the compound is general formula III, where R1, R5, and R6 are methyl; R2 is a PEG group; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 3; p is 4; and n is 1.
- the compound is general formula III, where R1, R5, and R6 are methyl; R2 is a PEG group; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 4; p is 5; and n is 1.
- the compound is general formula III, where R1, R5, and R6 are methyl; R2 is a PEG group; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 5; p is 6; and n is 1.
- the compound is general formula III, where R1, R5, and R6 are methyl; R2 is a PEG group; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 0; p is 1; and n is 2.
- the compound is general formula III, where R1, R5, and R6 are methyl; R2 is a PEG group; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 1; p is 2; and n is 2.
- the compound is general formula III, where R1, R5, and R6 are methyl; R2 is a PEG group; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 2; p is 3; and n is 2.
- the compound is general formula III, where R1, R5, and R6 are methyl; R2 is a PEG group; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 3; p is 4; and n is 2.
- the compound is general formula III, where R1, R5, and R6 are methyl; R2 is a PEG group; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 4; p is 5; and n is 2.
- the compound is general formula III, where R1, R5, and R6 are methyl; R2 is a PEG group; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 5; p is 6; and n is 2.
- the compound is general formula III, where R1, R5, and R6 are methyl; R2 is a PEG group; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 0; p is 1; and n is 3.
- the compound is general formula III, where R1, R5, and R6 are methyl; R2 is a PEG group; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 1; p is 2; and n is 3.
- the compound is general formula III, where R1, R5, and R6 are methyl; R2 is a PEG group; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 2; p is 3; and n is 3.
- the compound is general formula III, where R1, R5, and R6 are methyl; R2 is a PEG group; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 3; p is 4; and n is 3.
- the compound is general formula III, where R1, R5, and R6 are methyl; R2 is a PEG group; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 4; p is 5; and n is 3.
- the compound is general formula III, where R1, R5, and R6 are methyl; R2 is a PEG group; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 5; p is 6; and n is 3.
- the compound is general formula III where R5 and R6 are methyl; R1 and R2 are a PEG group; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 0; p is 1; and n is 1.
- the compound is general formula III where R5 and R6 are methyl; R1 and R2 are a PEG group; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 1; p is 2; and n is 1.
- the compound is general formula III where R5 and R6 are methyl; R1 and R2 are a PEG group; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 2; p is 3; and n is 1.
- the compound is general formula III where R5 and R6 are methyl; R1 and R2 are a PEG group; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 3; p is 4; and n is 1.
- the compound is general formula III where R5 and R6 are methyl; R1 and R2 are a PEG group; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 4; p is 5; n is 1.
- the compound is general formula III where R5 and R6 are methyl; R1 and R2 are a PEG group; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 5; p is 6; n is 1.
- the compound is general formula III, where R5 and R6 are methyl; R1 and R2 are a PEG group; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 0; p is 1; and n is 2.
- the compound is general formula III, where R5 and R6 are methyl; R1 and R2 are a PEG group; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 1; p is 2; and n is 2.
- the compound is general formula III, where R5 and R6 are methyl; R1 and R2 are a PEG group; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 2; p is 3; and n is 2.
- the compound is general formula III, where R5 and R6 are methyl; R1 and R2 are a PEG group; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 3; p is 4; and n is 2.
- the compound is general formula III, where R5 and R6 are methyl; R1 and R2 are a PEG group; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 4; p is 5; and n is 2.
- the compound is general formula III, where R5 and R6 are methyl; R1 and R2 are a PEG group; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 5; p is 6; and n is 2.
- the compound is general formula III, where R5 and R6 are methyl; R1 and R2 are a PEG group; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 0; p is 1; and n is 3.
- the compound is general formula III, where R5 and R6 are methyl; R1 and R2 are a PEG group; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 1; p is 2; and n is 3.
- the compound is general formula III, where R5 and R6 are methyl; R1 and R2 are a PEG group; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 2; p is 3; and n is 3.
- the compound is general formula III, where R5 and R6 are methyl; R1 and R2 are a PEG group; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 3; p is 4; and n is 3.
- the compound is general formula III, where R5 and R6 are methyl; R1 and R2 are a PEG group; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 4; p is 5; and n is 3.
- the compound is general formula III, where R5 and R6 are methyl; R1 and R2 are a PEG group; R7 and R8 are sulfo; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 5; p is 6; and n is 3.
- the compound is general formula III, where R5 and R6 are methyl; R1 and R2 are a PEG group; R7 is sulfo; R8 is sulfonamide —SO 2 NH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 0; p is 1; and n is 1.
- the compound is general formula III, where R5 and R6 are methyl; R1 and R2 are a PEG group; R7 is sulfo; R8 is sulfonamide —SO 2 NH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 1; p is 2; and n is 1.
- the compound is general formula III, where R5 and R6 are methyl; R1 and R2 are a PEG group; R7 is sulfo; R8 is sulfonamide —SO 2 NH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 2; p is 3; and n is 1.
- the compound is general formula III, where R5 and R6 are methyl; R1 and R2 are a PEG group; R7 is sulfo; R8 is sulfonamide —SO 2 NH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 3; p is 4; and n is 1.
- the compound is general formula III, where R5 and R6 are methyl; R1 and R2 are a PEG group; R7 is sulfo; R8 is sulfonamide —SO 2 NH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 4; p is 5; and n is 1.
- the compound is general formula III, where R5 and R6 are methyl; R1 and R2 are a PEG group; R7 is sulfo; R8 is sulfonamide —SO 2 NH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 5; p is 6; and n is 1.
- the compound is general formula III, where R5 and R6 are methyl; R1 and R2 are a PEG group; R7 is sulfo; R8 is sulfonamide —SO 2 NH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 0; p is 1; and n is 2.
- the compound is general formula III, where R5 and R6 are methyl; R1 and R2 are a PEG group; R7 is sulfo; R8 is sulfonamide —SO 2 NH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 1; p is 2; and n is 2.
- the compound is general formula III, where R5 and R6 are methyl; R1 and R2 are a PEG group; R7 is sulfo; R8 is sulfonamide —SO 2 NH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 2; p is 3; and n is 2.
- the compound is general formula III, where R5 and R6 are methyl; R1 and R2 are a PEG group; R7 is sulfo; R8 is sulfonamide —SO 2 NH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 3; p is 4; and n is 2.
- the compound is general formula III, where R5 and R6 are methyl; R1 and R2 are a PEG group; R7 is sulfo; R8 is sulfonamide —SO 2 NH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 4; p is 5; and n is 2.
- the compound is general formula III, where R5 and R6 are methyl; R1 and R2 are a PEG group; R7 is sulfo; R8 is sulfonamide —SO 2 NH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 5; p is 6; and n is 2.
- the compound is general formula III, where R5 and R6 are methyl; R1 and R2 are a PEG group; R7 is sulfo; R8 is sulfonamide —SO 2 NH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 0; p is 1; and n is 3.
- the compound is general formula III, where R5 and R6 are methyl; R1 and R2 are a PEG group; R7 is sulfo; R8 is sulfonamide —SO 2 NH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 1; p is 2; and n is 3.
- the compound is general formula III, where R5 and R6 are methyl; R1 and R2 are a PEG group; R7 is sulfo; R8 is sulfonamide —SO 2 NH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 2; p is 3; and n is 3.
- the compound is general formula III, where R5 and R6 are methyl; R1 and R2 are a PEG group; R7 is sulfo; R8 is sulfonamide —SO 2 NH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 3; p is 4; and n is 3.
- the compound is general formula III, where R5 and R6 are methyl; R1 and R2 are a PEG group; R7 is sulfo; R8 is sulfonamide —SO 2 NH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 4; p is 5; and n is 3.
- the compound is general formula III, where R5 and R6 are methyl; R1 and R2 are a PEG group; R7 is sulfo; R8 is sulfonamide —SO 2 NH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 5; p is 6; and n is 3.
- the compound is general formula III, where R5 and R6 are methyl; R1 and R2 are a PEG group; R7 is sulfo; R8 is a carboxamide group —CONH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 0; p is 1; and n is 1.
- the compound is general formula III, where R5 and R6 are methyl; R1 and R2 are a PEG group; R7 is sulfo; R8 is a carboxamide group —CONH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 1; p is 2; and n is 1.
- the compound is general formula III, where R5 and R6 are methyl; R1 and R2 are a PEG group; R7 is sulfo; R8 is a carboxamide group —CONH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 2; p is 3; and n is 1.
- the compound is general formula III, where R5 and R6 are methyl; R1 and R2 are a PEG group; R7 is sulfo; R8 is a carboxamide group —CONH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 3; p is 4; and n is 1.
- the compound is general formula III, where R5 and R6 are methyl; R1 and R2 are a PEG group; R7 is sulfo; R8 is a carboxamide group —CONH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 4; p is 5; and n is 1.
- the compound is general formula III, where R5 and R6 are methyl; R1 and R2 are a PEG group; R7 is sulfo; R8 is a carboxamide group —CONH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 5; p is 6; and n is 1.
- the compound is general formula III, where R5 and R6 are methyl; R1 and R2 are a PEG group; R7 is sulfo; R8 is a carboxamide group —CONH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 0; p is 1; and n is 2.
- the compound is general formula III, where R5 and R6 are methyl; R1 and R2 are a PEG group; R7 is sulfo; R8 is a carboxamide group —CONH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 1; p is 2; and n is 2.
- the compound is general formula III, where R5 and R6 are methyl; R1 and R2 are a PEG group; R7 is sulfo; R8 is a carboxamide group —CONH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 2; p is 3; and n is 2.
- the compound is general formula III, where R5 and R6 are methyl; R1 and R2 are a PEG group; R7 is sulfo; R8 is a carboxamide group —CONH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 3; p is 4; and n is 2.
- the compound is general formula III, where R5 and R6 are methyl; R1 and R2 are a PEG group; R7 is sulfo; R8 is a carboxamide group —CONH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 4; p is 5; and n is 2.
- the compound is general formula III, where R5 and R6 are methyl; R1 and R2 are a PEG group; R7 is sulfo; R8 is a carboxamide group —CONH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 5; p is 6; and n is 2.
- the compound is general formula III, where R5 and R6 are methyl; R1 and R2 are a PEG group; R7 is sulfo; R8 is a carboxamide group —CONH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 0; p is 1; and n is 3.
- the compound is general formula III, where R5 and R6 are methyl; R1 and R2 are a PEG group; R7 is sulfo; R8 is a carboxamide group —CONH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 1; p is 2; and n is 3.
- the compound is general formula III, where R5 and R6 are methyl; R1 and R2 are a PEG group; R7 is sulfo; R8 is a carboxamide group —CONH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 2; p is 3; and n is 3.
- the compound is general formula III, where R5 and R6 are methyl; R1 and R2 are a PEG group; R7 is sulfo; R8 is a carboxamide group —CONH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 3; p is 4; and n is 3.
- the compound is general formula III, where R5 and R6 are methyl; R1 and R2 are a PEG group; R7 is sulfo; R8 is a carboxamide group —CONH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 4; p is 5; and n is 3.
- the compound is general formula III, where R5 and R6 are methyl; R1 and R2 are a PEG group; R7 is sulfo; R8 is a carboxamide group —CONH—P where P is a PEG group; X is —OH, —NHS, —O-TFP, or —NR-L-maleimide; m is 5; p is 6; and n is 3.
- the compound is 550 Compound 1/2
- the methyl group on the ethylene glycol prevents the terminal —OH from oxidation. Oxidation is known to occur, overtime, on an unprotected terminus of an ethylene glycol group, diethylene glycol group, or (poly)ethylene glycol group, collectively referred to herein as an unprotected PEG terminus. Adding a methyl ether provides this protection, and prevents reaction with electrophilic reactive groups.
- the inventive compounds are activated.
- Activation of the compound adds a chemical moiety such that the compound is in a form that can be conjugated to a biological moiety. Examples of chemical moieties for activation are described below with reference to activation of 550 Compound 1, but one skilled in the art appreciates that activation is not limited to these examples.
- One non-limiting example of an activated compound is the NHS-ester of 550 Compound 1/2, shown below:
- the compound is a NHS-ester of 550 Compound 1/2 where, according to general formula I, o is 1, shown below:
- the compound is an NHS-ester of 550 Compound 1/2 where, according to general formula I, o is 5, shown below:
- an activated 550 Compound 1/2 is a tetrafluorophenyl (TFP)-ester form of 550 Compound 1, shown below:
- an activated 550 Compound 1/2 is a sulfotetrafluorophenyl (STP)-ester form of 550 Compound 1, shown below:
- an activated 550 Compound 1/2 is a hydrazide form of 550 Compound 1,
- an activated 550 Compound 1/2 is a maleimide form of 550 Compound 1, shown below:
- the compound is 550 Compound 2/2
- 550 Compound 2/2 (1-(5-carboxypentyl)-2-((1E,3E)-3-(1-(2-(2-methoxyethoxy)ethyl)-3-methyl-5-sulfonato-3-(3-sulfonatopropyl)indolin-2-ylidene)prop-1-enyl)-3-(2-methoxyethyl)-3-methyl-3H-indolium-5-sulfonate) contains a diethylene glycol on the indole N of the left heterocycle.
- 550 Compound 2/2, with the diethylene glycol shown in abbreviated notation used throughout, represents the following structure.
- 550 Compound 2/2 is activated as described above, one non-limiting example of which is the NHS-ester form of 550 Compound 2/2, shown below.
- the compound is 550 Compound 3/2
- methyl group on the ethylene glycol prevents the terminal —OH from oxidation. Oxidation is known to occur, over time, on an unprotected PEG terminus. Adding a methyl ether provides this protection, and prevents reaction with electrophilic reactive groups.
- 550 Compound 3/2 is activated as described above.
- the compound is 550 Compound 4/2
- methyl group on the ethylene glycol prevents the terminal —OH from oxidation. Oxidation is known to occur, over time, on an unprotected PEG terminus. Adding a methyl ether provides this protection, and prevents reaction with electrophilic reactive groups.
- 550 Compound 4/2 is activated as described above.
- the compound is 550 Compound 5/2
- methyl group on the ethylene glycol prevents the terminal —OH from oxidation. Oxidation is known to occur, over time, on an unprotected PEG terminus. Adding a methyl ether provides this protection, and prevents reaction with electrophilic reactive groups.
- 550 Compound 5/2 is activated as described above.
- the compound is 550 Compound 6/2
- methyl group on the ethylene glycol prevents the terminal —OH from oxidation. Oxidation is known to occur, over time, on an unprotected PEG terminus. Adding a methyl ether provides this protection, and prevents reaction with electrophilic reactive groups.
- 550 Compound 6/2 is activated as described above.
- the degree of sulfonation is varied to, e.g., vary the compound's degree of hydrophilicity or hydrophobicity.
- One non-limiting example is a monosulfonate form of 550 Compound 1/2, shown below, but it is understood that the single sulfo group can be at any of the described positions:
- the compound contains one or more substitutions of the polymethine linker.
- the compound has general formula IVa with “a” indicating an ethylene glycol, diethylene glycol, or (poly)ethylene glycol group on the left indole N, and the chain on the right indole N terminating in COX:
- each of R 1 , R 2 , R 5 , and R 6 is the same or different and is independently selected from the group consisting of an aliphatic, heteroaliphatic, sulfoalkyl, heteroaliphatic with terminal SO 3 , a PEG group P-L-Z where P is selected from an ethylene glycol group, a diethylene glycol group, and a (poly)ethylene glycol group where the (poly)ethylene glycol group is (CH 2 CH 2 O) s where s is an integer from 3-6 inclusive, a sulfonamide group -L-SO 2 NH—P-L-Z, and a carboxamide group -L-CONH—P-L-Z; each of R 7 and R 8 is the same or different and is independently selected from either H, SO 3 , a PEG group P-L-Z where P is selected from an ethylene glycol group, a diethylene glycol group, and a (poly)ethylene glycol group, where the (poly)ethylene glycol group
- One non-limiting example is a substituted polymethine form of 550 Compound 1/2, shown below:
- One non-limiting example is a substituted polymethine form of 550 Compound 2/2, shown below:
- One non-limiting example is a substituted polymethine form of 550 Compound 3/2, shown below:
- One non-limiting example is a substituted polymethine form of 550 Compound 4/2, shown below:
- One non-limiting example is a substituted polymethine form of 550 Compound 5/2, shown below:
- One non-limiting example is a substituted polymethine form of 550 Compound 6/2, shown below:
- One non-limiting example is a substituted polymethine form of 550 having an ethylene glycol, diethylene glycol, or (poly)ethylene glycol as described for general formula IV, such as the compound shown below:
- an ethylene glycol group, diethylene glycol group, and/or a (poly)ethylene glycol group which will collectively be referred to as a PEG group, unless specifically defined, may be present at position(s) in addition to such groups being present on the indole N atom(s).
- PEG-substituted compound is a 550 Compound 1/2 according to general formula II where R1 is an ethylene glycol group terminating with a methyl group, shown below:
- PEG-substituted compound is a 550 Compound 1/2 according to general formula II where R1 is a diethylene glycol group terminating with a methyl group, shown below:
- PEG-substituted compound is a 550 Compound 1/2 according to general formula II where R1 is a (poly)ethylene glycol (3) group terminating with a methyl group, shown below:
- PEG-substituted compound is a 550 Compound 1/2 according to general formula II where R1 is a (poly)ethylene glycol (4) group terminating with a methyl group, shown below:
- PEG-substituted compound is a 550 Compound 1/2 according to general formula II where R1 is a (poly)ethylene glycol (5) group terminating with a methyl group, shown below:
- PEG-substituted compound is a 550 Compound 1/2 according to general formula II where R1 is a (poly)ethylene glycol (6) group terminating with a methyl group, shown below:
- PEG-substituted compound is a 550 Compound 1/2 according to general formula II where R1 is a sulfonamide group -L-SO 2 NH—P—Z where Z is a methyl group, shown below:
- PEG-substituted compound is a 550 Compound 1/2 according to general formula II where R1 is a carboxamide group -L-CONH—P—Z where Z is a methyl group, shown below:
- PEG-substituted compound is a 550 Compound 1/2 according to general formula II where R2 is an ethylene glycol group terminating with a methyl group, shown below:
- PEG-substituted compound is a 550 Compound 1/2 according to general formula II where R2 is a diethylene glycol group terminating with a methyl group, shown below:
- PEG-substituted compound is a 550 Compound 1/2 according to general formula II where R2 is a (poly)ethylene glycol (3) group terminating with a methyl group, shown below:
- PEG-substituted compound is a 550 Compound 1/2 according to general formula II where R2 is a (poly)ethylene glycol (4) group terminating with a methyl group, shown below:
- PEG-substituted compound is a 550 Compound 1/2 according to general formula II where R2 is a (poly)ethylene glycol (5) group terminating with a methyl group, shown below:
- PEG-substituted compound is a 550 Compound 1/2 according to general formula II where R2 is a (poly)ethylene glycol (6) group terminating with a methyl group, shown below:
- PEG-substituted compound is a 550 Compound 1/2 according to general formula II where R2 is a sulfonamide group -L-SO 2 NH—P—Z where Z is a methyl group, shown below:
- PEG-substituted compound is a 550 Compound 1/2 according to general formula II where R2 is a carboxamide group -L-CONH—P—Z where Z is a methyl group, shown below:
- PEG-substituted compound is a 550 Compound 1/3 according to general formula II where both R1 and R2 are an ethylene glycol group terminating with a methyl group, shown below:
- PEG-substituted compound is a 550 Compound 1/3 according to general formula II where both R1 and R2 are a diethylene glycol group terminating with a methyl group, shown below:
- PEG-substituted compound is a 550 Compound 1/3 according to general formula II where both R1 and R2 are a (poly)ethylene glycol (3) group terminating with a methyl group, shown below:
- PEG-substituted compound is a 550 Compound 1/3 according to general formula II where both R1 and R2 are a (poly)ethylene glycol (4) group terminating with a methyl group, shown below:
- an additionally PEG-substituted compound is a 550 Compound 4/4 according to general formula III where both R1 and R2 are a (poly)ethylene glycol (4) group terminating with a methyl group, and R7 and R8 are sulfo, shown below:
- an additionally PEG-substituted compound is a 550 Compound 4/4 according to general formula III where both R1 and R2 are a (poly)ethylene glycol (4) group terminating with a methyl group, and R7 and R8 are H, shown below:
- PEG-substituted compound is a 550 Compound 1/3 according to general formula II where both R1 and R2 are a (poly)ethylene glycol (5) group terminating with a methyl group, shown below:
- PEG-substituted compound is a 550 Compound 1/3 according to general formula II where both R1 and R2 are a (poly)ethylene glycol (6) group terminating with a methyl group, shown below:
- PEG-substituted compound is a 550 Compound 1/2 according to general formula II where R8 is an ethylene glycol group terminating with a methyl group, shown below:
- PEG-substituted compound is a 550 Compound 1/2 according to general formula II where R8 is sulfonamide —SO 2 NH—P—Z where Z is a methyl group, shown below:
- PEG-substituted compound is a 550 Compound 1/2 according to general formula II where R8 is carboxamide —CONH—P—Z where Z is a methyl group, shown below:
- PEG-substituted compound is a 550 Compound 1/2 according to general formula II where R7 is an ethylene glycol group terminating with a methyl group, shown below:
- PEG-substituted compound is a 550 Compound 1/2 according to general formula II where R7 is a sulfonamide group —SO 2 NH—P—Z where Z is a methyl group, shown below:
- PEG-substituted compound is a 550 Compound 1/2 according to general formula II where R7 is a carboxamide group —CONH—P—Z where Z is a methyl group, shown below:
- PEG-substituted compound is a 550 Compound 1/3 according to general formula II where both R7 and R8 are an ethylene glycol group terminating with a methyl group, shown below:
- PEG-substituted compound is a 550 Compound 1/3 according to general formula II where both R7 and R8 are a sulfonamide group —SO 2 NH—P—Z where Z is a methyl group, shown below:
- PEG-substituted compound is a 550 Compound 1/3 according to general formula II where both R7 and R8 are a carboxamide group —CONH—P—Z where Z is a methyl group, shown below:
- the compound is 650 Compound 1/2
- Compound 1/2 ((2-((1E,3E,5E)-5-(1-(5-carboxypentyl)-3-(2-methoxyethyl)-3-methyl-5-sulfonatoindolin-2-ylidene)penta-1,3-dienyl)-1-(2-methoxyethyl)-3-methyl-3-(3-sulfonatopropyl)-3H-indolium-5-sulfonate tri sodium salt) contains an ethylene glycol on the indole N of the left heterocycle, i.e., a methylated ethylene glycol. The methyl group on the ethylene glycol prevents the terminal —OH from oxidation.
- Oxidation is known to occur, over time, on an unprotected PEG terminus (i.e., an unprotected ethylene glycol group, diethylene glycol group, or (poly)ethylene glycol group). Adding a methyl ether provides this protection, and prevents reaction with electrophilic reactive groups.
- the inventive compounds are activated.
- Activation of the compound adds a chemical moiety such that the compound is in a form that can be conjugated to a biological moiety.
- Examples of chemical moieties for activation are described below with reference to activation of 650 Compound 1, but one skilled in the art appreciates that activation is not limited to these examples.
- One non-limiting example of an activated compound is the NHS-ester of 650 Compound 1/2, shown below:
- the compound is a NHS-ester of 650 Compound 1/2 where, according to general formula I, o is 1, shown below:
- the compound is an NHS-ester of 650 Compound 1/2 where, according to general formula I, o is 5, shown below:
- an activated 650 Compound 1/2 is the tetrafluorophenyl (TFP)-ester of 650 Compound 1/2, shown below:
- an activated 650 Compound 1/2 is the sulfotetrafluorophenyl (STP)-ester of 650 Compound 1/2, shown below:
- an activated 650 Compound 1/2 is the hydrazide of 650 Compound 1, shown below:
- an activated 650 Compound 1/2 is the maleimide of 650 Compound 1, shown below:
- the compound is 650 Compound 2/2
- Oxidation is known to occur, over time, on an unprotected PEG terminus. Adding a methyl ether provides this protection, and prevents reaction with electrophilic reactive groups.
- 650 Compound 2/2 is activated as described above, one non-limiting example of which is the NHS-ester form of 650 Compound 2/2, shown below.
- the compound is 650 Compound 3/2
- Oxidation is known to occur, over time, on an unprotected PEG terminus. Adding a methyl ether provides this protection, and prevents reaction with electrophilic reactive groups.
- 650 Compound 3/2 is activated as described above, one non-limiting example of which is the NHS-ester form of 650 Compound 3/2, shown below.
- the compound is 650 Compound 4/2
- Oxidation is known to occur, over time, on an unprotected PEG terminus. Adding a methyl ether provides this protection, and prevents reaction with electrophilic reactive groups.
- 650 Compound 4/2 is activated as described above.
- the compound is 650 Compound 5/2
- Oxidation is known to occur, over time, on an unprotected PEG terminus. Adding a methyl ether provides this protection, and prevents reaction with electrophilic reactive groups.
- 650 Compound 5/2 is activated as described above.
- the compound is 650 Compound 6/2
- Oxidation is known to occur, over time, on an unprotected PEG terminus. Adding a methyl ether provides this protection, and prevents reaction with electrophilic reactive groups.
- 650 Compound 6/2 is activated as described above.
- the compound contains one or more substitutions of the polymethine linker.
- the compound has general formula Va
- each of R 1 , R 2 , R 5 , and R 6 is the same or different and is independently selected from the group consisting of an aliphatic, heteroaliphatic, sulfoalkyl group, heteroaliphatic with terminal SO 3 , a PEG group P-L-Z where P is selected from an ethylene glycol group, a diethylene glycol group, and a (poly)ethylene glycol group, where the (poly)ethylene glycol group is (CH 2 CH 2 O) s , where s is an integer from 3-6 inclusive, a sulfonamide group -L-SO 2 NH—P-L-Z, and a carboxamide group -L-CONH—P-L-Z; each of R 7 and R 8 is the same or different and is independently selected from either H, SO 3 , a PEG group P-L-Z where P is selected from an ethylene glycol group, a diethylene glycol group, and a (poly)ethylene glycol group where the (poly)ethylene
- each of R 1 , R 2 , R 5 , and R 6 is the same or different and is independently selected from the group consisting of an aliphatic, heteroaliphatic, sulfoalkyl group, heteroaliphatic with terminal SO 3 , a PEG group P-L-Z where P is selected from an ethylene glycol group, a diethylene glycol group, and a (poly)ethylene glycol group, where the (poly)ethylene glycol group is (CH 2 CH 2 O) s , where s is an integer from 3-6 inclusive, a sulfonamide group -L-SO 2 NH—P-L-Z, and a carboxamide group -L-CONH—P-L-Z; each of R 7 and R 8 is the same or different and is independently selected from either H, SO 3 , a PEG group P-L-Z where P is selected from an ethylene glycol group, a diethylene glycol group, and a (poly)ethylene glycol group where the (poly)ethylene
- One non-limiting example is a substituted polymethine form of 650 Compound 1/2, shown below:
- One non-limiting example is a substituted polymethine form of 650 Compound 2/2, shown below:
- One non-limiting example is a substituted polymethine form of 650 Compound 3/2, shown below:
- One non-limiting example is a substituted polymethine form of 650 Compound 4/2, shown below:
- One non-limiting example is a substituted polymethine form of 650 Compound 5/2, shown below:
- One non-limiting example is a substituted polymethine form of 650 Compound 6/2, shown below:
- One non-limiting example is a substituted polymethine form of 650 Compound 1/3 having an ethylene glycol, diethylene glycol, or (poly)ethylene glycol as described for general formula V, such as the compound shown below:
- One non-limiting example is a substituted polymethine form of 650 Compound 1/2, shown below:
- One non-limiting example is a substituted polymethine form of 650 Compound 2/2, shown below:
- One non-limiting example is a substituted polymethine form of 650 Compound 3/2, shown below:
- One non-limiting example is a substituted polymethine form of 650 Compound 4/2, shown below:
- One non-limiting example is a substituted polymethine form of 650 Compound 5/2, shown below:
- One non-limiting example is a substituted polymethine form of 650 Compound 6/2, shown below:
- One non-limiting example is a substituted polymethine form of 650 Compound 1/3 having an ethylene glycol, diethylene glycol, or (poly)ethylene glycol as described for general formula V, such as the compound shown below:
- the degree of sulfonation is varied to, e.g., vary the compound's degree of hydrophilicity or hydrophobicity.
- One non-limiting example is a monosulfonate form of 650 Compound 1/2, shown below, but it is understood that the single sulfo group can be at any of the described positions:
- an ethylene glycol group, diethylene glycol group, and/or a (poly)ethylene glycol group which will collectively be referred to as a PEG group, unless specifically defined, may be present at position(s) in addition to such groups being present on the N atom(s) of the indole structure.
- PEG-substituted compound is a 650 Compound 1/2 according to general formula II where R1 is an ethylene glycol group terminating with a methyl group, shown below:
- PEG-substituted compound is a 650 Compound 1/2 according to general formula II where R1 is a diethylene glycol group terminating with a methyl group, shown below:
- PEG-substituted compound is a 650 Compound 1/2 according to general formula II where R1 is a (poly)ethylene glycol (3) group terminating with a methyl
- PEG-substituted compound is a 650 Compound 1/2 according to general formula II where R1 is a (poly)ethylene glycol (4) group terminating with a methyl group, shown below:
- PEG-substituted compound is a 650 Compound 1/2 according to general formula II where R1 is a (poly)ethylene glycol (5) group terminating with a methyl group, shown below:
- PEG-substituted compound is a 650 Compound 1/2 according to general formula II where R1 is a (poly)ethylene glycol (6) group terminating with a methyl group, shown below:
- PEG-substituted compound is a 650 Compound 1/2 according to general formula II where R1 is a sulfonamide group -L-SO 2 NH—P—Z where Z is a methyl group, shown below:
- PEG-substituted compound is a 650 Compound 1/2 according to general formula II where R1 is a carboxamide group -L-CONH—P—Z where Z is a methyl group, shown below:
- PEG-substituted compound is a 650 Compound 1/2 according to general formula II where R2 is an ethylene glycol group terminating with a methyl group, shown below:
- PEG-substituted compound is a 650 Compound 1/2 according to general formula II where R2 is a diethylene glycol group terminating with a methyl group, shown below:
- PEG-substituted compound is a 650 Compound 1/2 according to general formula II where R2 is a (poly)ethylene glycol (3) group terminating with a methyl group, shown below:
- PEG-substituted compound is a 650 Compound 1/2 according to general formula II where R2 is a (poly)ethylene glycol (4) group terminating with a methyl group, shown below:
- PEG-substituted compound is a 650 Compound 1/2 according to general formula II where R2 is a (poly)ethylene glycol (5) group terminating with a methyl group, shown below:
- PEG-substituted compound is a 650 Compound 1/2 according to general formula II where R2 is a (poly)ethylene glycol (6) group terminating with a methyl group, shown below:
- PEG-substituted compound is a 650 Compound 1/2 according to general formula II where R2 is a sulfonamide group -L-SO 2 NH—P—Z where Z is a methyl group, shown below:
- PEG-substituted compound is a 650 Compound 1/2 according to general formula II where R2 is a carboxamide group -L-CONH—P—Z where Z is a methyl group, shown below:
- PEG-substituted compound is a 650 Compound 1/3 according to general formula II where both R1 and R2 are an ethylene glycol group terminating with a methyl group, shown below:
- PEG-substituted compound is a 650 Compound 1/3 according to general formula II where both R1 and R2 are a diethylene glycol group terminating with a methyl group, shown below:
- PEG-substituted compound is a 650 Compound 1/3 according to general formula II where both R1 and R2 are a (poly)ethylene glycol (3) group terminating with a methyl group, shown below:
- PEG-substituted compound is a 650 Compound 1/3 according to general formula II where both R1 and R2 are a (poly)ethylene glycol (4) group terminating with a methyl group, shown below:
- an additionally PEG-substituted compound is a 650 Compound 4/4 according to general formula III where both R1 and R2 are a (poly)ethylene glycol (4) group terminating with a methyl group, and R7 and R8 are sulfo, shown below:
- an additionally PEG-substituted compound is a 650 Compound 4/4 according to general formula III (V19-03005) where both R1 and R2 are a (poly)ethylene glycol (4) group terminating with a methyl group, and R7 and R8 are sulfo, shown below:
- an additionally PEG-substituted compound is a 650 Compound 4/4 according to general formula III where both R1 and R2 are a (poly)ethylene glycol (4) group terminating with a methyl group, and R7 and R8 are H, shown below:
- an additionally PEG-substituted compound is a 650 Compound 4/4 according to general formula III where both R1 and R2 are a (poly)ethylene glycol (4) group terminating with a methyl group, and R7 and R8 are H, shown below:
- PEG-substituted compound is a 650 Compound 1/3 according to general formula II where both R1 and R2 are a (poly)ethylene glycol (5) group terminating with a methyl group, shown below:
- PEG-substituted compound is a 650 Compound 1/3 according to general formula II where both R1 and R2 are a (poly)ethylene glycol (6) group terminating with a methyl group, shown below:
- PEG-substituted compound is a 650 Compound 1/3 according to general formula II where both R1 and R2 are a sulfonamide group -L-SO 2 NH—P—Z where Z is a methyl group, shown below:
- PEG-substituted compound is a 650 Compound 1/3 according to general formula II where both R1 and R2 are a carboxamide group -L-CONH—P—Z where Z is a methyl group, shown below:
- PEG-substituted compound is a 650 Compound 1/2 according to general formula II where R8 is an ethylene glycol group terminating with a methyl group, shown below:
- PEG-substituted compound is a 650 Compound 1/2 according to general formula II where R8 is sulfonamide —SO 2 NH—P—Z where Z is a methyl group, shown below:
- PEG-substituted compound is a 650 Compound 1/2 according to general formula II where R8 is carboxamide —CONH—P—Z where Z is a methyl group, shown below:
- PEG-substituted compound is a 650 Compound 1/2 according to general formula II where R7 is an ethylene glycol group terminating with a methyl group, shown below:
- PEG-substituted compound is a 650 Compound 1/2 according to general formula II where R7 is a sulfonamide group —SO 2 NH—P—Z where Z is a methyl group, shown below:
- PEG-substituted compound is a 650 Compound 1/2 according to general formula II where R7 is a carboxamide group —CONH—P—Z where Z is a methyl group, shown below:
- PEG-substituted compound is a 650 Compound 1/3 according to general formula II where both R7 and R8 are an ethylene glycol group terminating with a methyl group, shown below:
- PEG-substituted compound is a 650 Compound 1/3 according to general formula II where both R7 and R8 are a sulfonamide group —SO 2 NH—P—Z where Z is a methyl group, shown below:
- PEG-substituted compound is a 650 Compound 1/3 according to general formula II where both R7 and R8 are a carboxamide group —CONH—P—Z where Z is a methyl group, shown below:
- the compound is 755 Compound 1/2
- Oxidation is known to occur, over time, on an unprotected PEG terminus (i.e., an unprotected terminus of an ethylene glycol group, diethylene glycol group, or (poly)ethylene glycol group). Adding a methyl ether provides this protection, and prevents reaction with electrophilic reactive groups.
- the inventive compounds are activated.
- Activation of the compound adds a chemical moiety such that the compound is in a form that can be conjugated to a biological moiety.
- Examples of chemical moieties for activation are described below with reference to activation of 755 Compound 1/2, but one skilled in the art appreciates that activation is not limited to these examples.
- One non-limiting example of an activated compound is the NHS-ester of 755 Compound 1/2, shown below:
- the compound is an NHS-ester of 755 Compound 1/2 where, according to general formula I, o is 1, shown below:
- the compound is an NHS-ester of 755 Compound 1/2 where, according to general formula I, o is 5, shown below:
- an activated 755 Compound 1/2 is a tetrafluorophenyl (TFP)-ester form of 755 Compound 1/2, shown below:
- an activated 755 Compound 1/2 is a sulfotetrafluorophenyl (STP)-ester form of 755 Compound 1/2, shown below:
- an activated 755 Compound 1/2 is a hydrazide form of 755 Compound 1/2, shown below:
- an activated 755 Compound 1/2 is a maleimide form of 755 Compound 1/2
- the compound is 755 Compound 2/2
- Oxidation is known to occur, over time, on an unprotected PEG terminus. Adding a methyl ether provides this protection, and prevents reaction with electrophilic reactive groups.
- 755 Compound 2/2 is activated as described above, one non-limiting example of which is the NHS-ester form of 755 Compound 2/2, shown below.
- the compound is 755 Compound 3/2
- Oxidation is known to occur, over time, on an unprotected PEG terminus. Adding a methyl ether provides this protection, and prevents reaction with electrophilic reactive groups.
- 755 Compound 3/2 is activated as described above, one non-limiting example of which is the NHS-ester form of 755 Compound 3/2, shown below.
- the compound is 755 Compound 4/2
- the compound is 755 Compound 4/2E,3E,5E,7E)-7-(3-methyl-5-sulfonato-3-(3-sulfonatopropyl)-1-(2,5,8,11-tetraoxatridecan-13-yl)indolin-2-ylidene)hepta-1,3,5-trienyl)-3H-indolium-5-sulfonate) contains a (poly)ethylene glycol on the indole N of the left heterocycle. The methyl group on the ethylene glycol prevents the terminal —OH from oxidation. Oxidation is known to occur, over time, on an unprotected PEG terminus. Adding a methyl ether provides this protection, and prevents reaction with electrophilic reactive groups. For functional assays, 755 Compound 4/2 is activated as described above.
- the compound is 755 Compound 5/2
- Oxidation is known to occur, over time, on an unprotected PEG terminus. Adding a methyl ether provides this protection, and prevents reaction with electrophilic reactive groups.
- 755 Compound 5/2 is activated as described above.
- the compound is 755 Compound 6/2
- Oxidation is known to occur, over time, on an unprotected PEG terminus. Adding a methyl ether provides this protection, and prevents reaction with electrophilic reactive groups.
- 755 Compound 6/2 is activated as described above.
- the compound contains one or more substitutions of the polymethine linker.
- the compound has general formula VIa with “a” indicating an ethylene glycol, diethylene glycol, or (poly)ethylene glycol group on the left indole N, and the chain on the right indole N terminating in COX:
- each of R 1 , R 2 , R 5 , and R 6 is the same or different and is independently selected from the group consisting of an aliphatic, heteroaliphatic, sulfoalkyl group, heteroaliphatic with terminal SO 3 , a PEG group P-L-Z where P is selected from an ethylene glycol group, a diethylene glycol group, and a (poly)ethylene glycol group, where the (poly)ethylene glycol group is (CH 2 CH 2 O) s , where s is an integer from 3-6 inclusive, a sulfonamide group -L-SO 2 NH—P-L-Z, and a carboxamide group -L-CONH—P-L-Z; each of R 7 and R 8 is the same or different and is independently selected from either H, SO 3 , a PEG group P-L-Z where P is selected from an ethylene glycol group, a diethylene glycol group, and a (poly)ethylene glycol group, where the (poly)
- the compound of general formula VI wherein R3 and R4 together form a cyclic structure where R3 and R4 are joined using a divalent structural element of —(CH 2 ) q —, where q is 3, to result in a 6-membered ring, and Y is OR PM where R PM is a substituted 6-membered aryl group, where the substituted group is sulfo.
- One non-limiting example is a substituted polymethine form of 755 Compound 1/3 having an ethylene glycol, diethylene glycol, or (poly)ethylene glycol as described for general formula VI, such as the compound shown below:
- One non-limiting example is a substituted polymethine form of 755 Compound 4/4 having an ethylene glycol, diethylene glycol, or (poly)ethylene glycol as described for general formula VI, such as the compound shown below:
- the degree of sulfonation is varied to, e.g., vary the compound's degree of hydroplilicity or hydrophobicity.
- One non-limiting example is a monosulfonate form of 755 Compound 1/2, shown below, but it is understood that the single sulfo group can be at any of the described positions:
- an ethylene glycol group, diethylene glycol group, and/or a (poly)ethylene glycol group which will collectively be referred to as a PEG group unless specifically defined, may be present at position(s) in addition to such groups being present on the N atom(s) of the indole structure.
- a PEG group a (poly)ethylene glycol group
- One non-limiting example of an additionally PEG-substituted compound is a 755 Compound 1/2 according to general formula II where R1 is an ethylene glycol group terminating with a methyl group, shown below:
- PEG-substituted compound is a 755 Compound 1/2 according to general formula II where R1 is a diethylene glycol group terminating with a methyl group, shown below:
- PEG-substituted compound is a 755 Compound 1/2 according to general formula II where R1 is a (poly)ethylene glycol (3) group terminating with a methyl group, shown below:
- PEG-substituted compound is a 755 Compound 1/2 according to general formula II where R1 is a (poly)ethylene glycol (4) group terminating with a methyl group, shown below:
- PEG-substituted compound is a 755 Compound 1/2 according to general formula II where R1 is a (poly)ethylene glycol (5) group terminating with a methyl group, shown below:
- PEG-substituted compound is a 755 Compound 1/2 according to general formula II where R1 is a (poly)ethylene glycol (6) group terminating with a methyl group, shown below:
- PEG-substituted compound is a 755 Compound 1/2 according to general formula II where R1 is a sulfonamide group -L-SO 2 NH—P—Z where Z is a methyl group, shown below:
- PEG-substituted compound is a 755 Compound 1/2 according to general formula II where R1 is a carboxamide group -L-CONH—P—Z where Z is a methyl group, shown below:
- PEG-substituted compound is a 755 Compound 1/2 according to general formula II where R2 is an ethylene glycol group terminating with a methyl group, shown below:
- PEG-substituted compound is a 755 Compound 1/2 according to general formula II where R2 is a diethylene glycol group terminating with a methyl group, shown below:
- PEG-substituted compound is a 755 Compound 1/2 according to general formula II where R2 is a (poly)ethylene glycol (3) group terminating with a methyl group, shown below:
- PEG-substituted compound is a 755 Compound 1/2 according to general formula II where R2 is a (poly)ethylene glycol (4) group terminating with a methyl group, shown below:
- PEG-substituted compound is a 755 Compound 1/2 according to general formula II where R2 is a (poly)ethylene glycol (5) group terminating with a methyl group, shown below:
- PEG-substituted compound is a 755 Compound 1/2 according to general formula II where R2 is a (poly)ethylene glycol (6) group terminating with a methyl group, shown below:
- PEG-substituted compound is a 755 Compound 1/2 according to general formula II where R2 is a sulfonamide group -L-SO 2 NH—P—Z where Z is a methyl group, shown below:
- PEG-substituted compound is a 755 Compound 1/2 according to general formula II where R2 is a carboxamide group -L-CONH—P—Z where Z is a methyl group, shown below:
- PEG-substituted compound is a 755 Compound 1/3 according to general formula II where both R1 and R2 are an ethylene glycol group terminating with a methyl group, shown below:
- PEG-substituted compound is a 755 Compound 1/3 according to general formula II where both R1 and R2 are a diethylene glycol group terminating with a methyl group, shown below:
- PEG-substituted compound is a 755 Compound 1/3 according to general formula II where both R1 and R2 are a (poly)ethylene glycol (3) group terminating with a methyl group, shown below:
- PEG-substituted compound is a 755 Compound 1/3 according to general formula II where both R1 and R2 are a (poly)ethylene glycol (4) group terminating with a methyl group, shown below:
- an additionally PEG-substituted compound is a 755 Compound 4/4 according to general formula II where both R1 and R2 are a (poly)ethylene glycol (4) group terminating with a methyl group, and R7 and R8 are sulfo, shown below:
- PEG-substituted compound is a 755 Compound 4/4 according to general formula II where both R1 and R2 are a (poly)ethylene glycol (4) group terminating with a methyl group, and R7 and R8 are H, shown below:
- PEG-substituted compound is a 755 Compound 1/3 according to general formula II where both R1 and R2 are a (poly)ethylene glycol (5) group terminating with a methyl group, shown below:
- PEG-substituted compound is a 755 Compound 1/3 according to general formula II where both R1 and R2 are a (poly)ethylene glycol (6) group terminating with a methyl group, shown below:
- PEG-substituted compound is a 755 Compound 1/3 according to general formula II where both R1 and R2 are a sulfonamide group -L-SO 2 NH—P—Z where Z is a methyl group, shown below:
- PEG-substituted compound is a 755 Compound 1/3 according to general formula II where both R1 and R2 are a carboxamide group -L-CONH—P—Z where Z is a methyl group, shown below:
- PEG-substituted compound is a 755 Compound 1/2 according to general formula II where R8 is an ethylene glycol group terminating with a methyl group, shown below:
- PEG-substituted compound is a 755 Compound 1/2 according to general formula II where R8 is sulfonamide —SO 2 NH—P—Z where Z is a methyl group, shown below:
- PEG-substituted compound is a 755 Compound 1/2 according to general formula II where R8 is carboxamide —CONH—P—Z where Z is a methyl group, shown below:
- PEG-substituted compound is a 755 Compound 1/2 according to general formula II where R7 is an ethylene glycol group terminating with a methyl group, shown below:
- PEG-substituted compound is a 755 Compound 1/2 according to general formula II where R7 is a sulfonamide group —SO 2 NH—P—Z where Z is a methyl group, shown below:
- PEG-substituted compound is a 755 Compound 1/2 according to general formula II where R7 is a carboxamide group —CONH—P—Z where Z is a methyl group, shown below:
- PEG-substituted compound is a 755 Compound 1/3 according to general formula II where both R7 and R8 are an ethylene glycol group terminating with a methyl group, shown below:
- PEG-substituted compound is a 755 Compound 1/3 according to general formula II where both R7 and R8 are a sulfonamide group —SO 2 NH—P—Z where Z is a methyl group, shown below:
- PEG-substituted compound is a 755 Compound 1/3 according to general formula II where both R7 and R8 are a carboxamide group —CONH—P—Z where Z is a methyl group, shown below:
- the disclosed compounds are used and are useful as chromophores and/or fluorophores.
- they can be used for optical labelling and, therefore, for the qualitative and/or quantitative detection of proteins, nucleic acids, oligomers, DNA, RNA, biological cells, lipids, mono-, oligo- and polysaccharides, ligands, receptors, polymers, drugs, polymeric beads, etc.
- inventive compounds containing the disclosed functionality or functionalities, may be synthesized using methods known in the art, e.g., as described as follows with all references expressly incorporated by reference herein in their entirety.
- the hydrophilicity or hydrophobicity of the inventive compounds is modified by the number and location of hydrophilic groups, such as sulfo, carboxy, hydroxy, etc., groups.
- the number and location of hydrophilic groups is symmetrical, such that the number and location of hydrophilic group(s) on one of the indoles of the inventive cyanine compound is also found on the other indole.
- at least one hydrophilic group is found on each of the indoles of the inventive cyanine compound.
- solubility, lack of aggregation, reactivity, lack of cross-reactivity, etc. are effected by the number and location of the disclosed functionality or functionalities on the compound.
- short PEG groups are added on opposite sides and opposite ends of indole cyanine compounds to effectively surround the hydrophobic core structure of the molecule.
- sulfonate groups are added to the outer phenyl rings of indole cyanine dyes along with the symmetrical placement of short PEG chains on opposite sides and opposite ends.
- PEG 1-6 group(s) are added on opposite sides and opposite ends of indole cyanine compounds to effectively surround the hydrophobic core structure of the molecule.
- sulfonate groups are added to the outer phenyl rings of indole cyanine dyes along with the symmetrical placement of short PEG chains on opposite sides and opposite ends.
- the compound is synthesized by a condensation reaction, known to one skilled in the art, of the two differently substituted indole heterocycles separated by a (poly)methine linker or bridge, e.g., C1, C3, or C5.
- a condensation reaction known to one skilled in the art
- the two differently substituted indole heterocycles separated by a (poly)methine linker or bridge, e.g., C1, C3, or C5.
- a condensation reaction known to one skilled in the art
- C1, C3, or C5 linker e.g., a (poly)methine linker or bridge
- Other synthesis methods are possible.
- one of the indole heterocycles is first reacted with the C1, C3, or C5 linker.
- the 1:1 condensation product is isolated, and then condensed with the second indole heterocycle to result in the cyanine compound.
- the sequence of reacting the indole heterocycles is irrelevant.
- Conjugates of the compounds were prepared by covalently coupling the compounds to a biomolecule using the functional substituent on the N-position of the indole ring. This functional substituent was activated by routine protein chemistry reaction methods known to one skilled in the art.
- the activated compound may be converted to, e.g, and without limitation, aN-hydroxysuccinimide (NHS)-ester, an acid fluoride, a tetrafluorophenyl (TFP)- or sulfotetrafluorophenyl (STP)-ester, an iodoacetyl group, a maleimide, a hydrazide, a sulfonyl chloride, or a phenylazide.
- Methods for preparing such compounds are known to one skilled in the art.
- the activated substituent was then reacted with an amino group on the biomolecule under conditions to conjugate the desired biomolecule.
- a non-activated carboxyl group on the N-position of the indole in the compound was coupled to an amine using a carbodimide.
- a hydroxyl group such as a terminal hydroxyl group
- a reactive derivative able to link with, for example, proteins and other molecules.
- activating groups include tosyl chloride (TsCl), tresyl chloride (TrCl), disuccinimidyl carbonate (DSC), divinyl sulfone, bis-epoxy compounds, carbonyl diimidazole (CDI), 2-fluoro-1-methylpyridinium (FMP), and trichloro-s-triazine (TsT).
- the hydroxyl group is activated to a succinimidyl carbonate, which is reactive with amines.
- Coupling between the compound and the biomolecule may be performed as follows.
- the compound was reacted with the biomolecule in an organic or aqueous solution at pH between pH 5-pH 12 inclusive.
- the compound need not be dissolved in an organic solvent, such as dimethyl formamide (DMF) or dimethyl sulfoxide (DMSO) prior to adding the biomolecule.
- coupling reaction may be performed in a 100% aqueous solution. In one embodiment, the coupling reaction occurs at room temperature (about 20° C. to about 22° C.).
- composition (dye) at least one biocompatible excipient was added to the compound(s), as known to one of ordinary skill in the art.
- Excipients include, but are not limited to, buffers, solubility enhancing agents, stabilizing agents, etc.
- a kit for performing an assay method comprises a disclosed compound, and instructions for performing the method using the compound.
- the disclosed activated compounds are useful to label macromolecules (e.g., antibodies, streptavidin, etc) using methods known to one skilled in the art, e.g., Hermanson, Bioconjugate Techniques, 2nd Ed., London, Elsevier Inc. 2008.
- the reaction was carried out for 1-2 h at room temperature (about 20° C. to about 22° C.), and then desalted by dialyzing against several changes of phosphate buffered saline (pH 7.2) or purified by gel filtration to remove the unreacted fluorescent dye.
- the resulting compound-biomolecule conjugate was used to detect, e.g., specific proteins in immunoassays, sugars in glycoproteins with lectins, protein-protein interactions, oligonucleotides in nucleic acid, hybridization, and in electrophoretic mobility shift assays (EMSA).
- specific proteins in immunoassays e.g., specific proteins in immunoassays, sugars in glycoproteins with lectins, protein-protein interactions, oligonucleotides in nucleic acid, hybridization, and in electrophoretic mobility shift assays (EMSA).
- ESA electrophoretic mobility shift assays
- the resulting compound-biomolecule conjugates exhibited fluorescent properties.
- they were used in optical methods including fluorescence optical qualitative and quantitative determination methods. Examples of such methods include, but are not limited to, microscopy, immunoassays, hybridization methods, chromatographic and electrophoretic methods, fluorescence resonance energy transfer (FRET) systems, bioluminescence reasonance energy transfer (BRET), high throughput screenings, analysis of receptor-ligand interactions on a microarray, etc.
- FRET fluorescence resonance energy transfer
- BRET bioluminescence reasonance energy transfer
- Recognition units are molecules having specificity and/or affinity for a specific group of molecules. Examples include, but are not limited to, antibodies that have affinity for antigens, enzymes that bind and/or react with a specific bond or bonds within a sequence of amino acids in a peptide or react with a substrate, cofactors such as metals that enhance or inhibit specific interactions, lectins that bind specific sugars or sugar sequences (e.g., oligosaccharides, polysaccharides, dextrans, etc.), biotin binding proteins such as avidin and streptavidin that bind biotin and biotinylated molecules, antibody binding proteins such as Protein A, Protein G, Protein A/G and Protein L, sequences of amino acids or metals that have affinity for each other (e.g., histidine sequences that bind nickel or copper, phosphate containing proteins that bind gallium, aluminium,
- inventive compounds and/or conjugates are used in optical, including fluorescence optical, qualitative and/or quantitative determination methods to diagnose properties of cells (molecular imaging), in biosensors (point of care measurements), for investigation of the genome, and in miniaturizing technologies.
- Microscopy, cytometry, cell sorting, fluorescence correlation spectroscopy (FCS), ultra high throughput screening (uHTS), multicolor fluorescence in situ hybridisation (mc-FISH), FRET-systems, BRET-systems, and microarrays (DNA- and protein-chips) are exemplary application fields.
- a microarray is a grid-like arrangement where more than two different molecules are immobilized in a known predefined region on at least one surface, and is useful to evaluate receptor ligand interactions.
- a receptor is a naturally occurring or synthetic molecule that exhibits an affinity to a given ligand.
- Receptors can be used in a pure form or bound to another specie. Receptors can be coupled covalently or noncovalently to a binding partner either directly or indirectly (e.g., through a coupling mediator).
- Receptor examples include, but are not limited to, agonists and antagonists for cell membrane receptors, toxins and other poisons, viral epitopes, hormones (e.g., opiates, steroids), hormone receptors, peptides, enzymes, enzyme substrates, drugs acting as cofactors, lectins, sugars, oligonucleotides, nucleic acids, oligosaccharides, cells, cell fragments, tissue fragments, proteins, antibodies, etc.
- a ligand is a molecule that is recognized by a certain receptor.
- Ligand examples include, but are not limited to, agonists and antagonists for cell membrane receptors, toxins and other poisons, viral epitopes, hormones (e.g., opiates, steroids), hormone receptors, peptides, enzymes, enzyme substrates, drugs acting as cofactors, lectins, sugars, oligonucleotides, nucleic acids, oligosaccharides, proteins, antibodies, etc.
- Example 1 Synthesis of 4-methyl-5-oxohexane sulfonic acid Used to Synthesize
- Example 2 compound 2,3-dimethyl-3-(3-sulfopropyl)-3H-indole-5-sulfonic acid di-potassium salt and
- Example 2 Synthesis of 2,3-dimethyl-3-(3-sulfopropyl)-3H-indole-5-sulfonic acid di-potassium salt Used to Synthesize Example 3 compound 1-(2-methoxy-ethyl)-2,3-dimethyl-5-sulfo-3-(3-sulfo-propyl)-3H-indolium and
- Example 4 compound 1-[2-(2-methoxy-ethoxy)-ethyl]-2,3-dimethyl-5-sulfo-3-(3-sulfo-propyl)-3H-indolium and
- Example 5 compound 1- ⁇ 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl ⁇ -2,3-dimethyl-5-sulfo-3-(3-sulfo-propyl)-3H-indolium and
- Example 7 compound 1-(5-carboxypentyl)-3-methyl-2-((E)-2-phenylamino-vinyl)-5-sulfo-3-(3-sulfo-propyl)-3H-indolium and
- Example 8 compound 1-(5-carboxypentyl)-3-methyl-2-((1E,3E)-4-phenylamino-buta-1,3-dienyl)-5-sulfo-3-(3-sulfopropyl)-3H-indolium and
- the residue was purified by column chromatography (RP-18, acetonitrile/water and concentrated HCl) to separate the diastereomers from each other.
- the diastereomer that first eluted from the column was termed diastereomer 1 (550 Compound 1 (isomer 1)).
- the diastereomer that eluted second from the column was termed diastereomer 2 (550 Compound 1 (isomer 2)).
- the diastereomers were separated, followed by neutralization and evaporation. Purification of the single diastereomeric compound was completed on a RP-18 column, acetonitrile/water. The corresponding fractions were pooled and the solvent was removed by distillation.
- the two products (diastereomers 550 Compound 1 (isomer 1) and 550 Compound 1 (isomer 2)) were dried in high vacuum.
- the residue was purified by column chromatography (RP-18, acetonitrile/water and concentrated HCl) to separate the diastereomers from each other.
- the diastereomer that first eluted from the column was termed diastereomer 1 (650 Compound 1 (isomer 1)).
- the diastereomer that eluted second from the column was termed diastereomer 2 (650 Compound 1 (isomer 2)).
- the diastereomers were separated, followed by neutralization and evaporation. Purification of the single diastereomeric compound was completed on a RP-18 column, acetonitrile/water. The corresponding fractions were pooled and the solvent was removed by distillation.
- the two products (diastereomers 650 Compound 1 (isomer 1) and 650 Compound 1 (isomer 2)) were dried in high vacuum.
- the residue was purified by column chromatography (RP-18, acetonitrile/water and concentrated HCl) to separate the diastereomers from each other.
- the diastereomer that first eluted from the column was termed diastereomer 1 (755 Compound 1 (isomer 1)).
- the diastereomer that eluted second from the column was termed diastereomer 2 (755 Compound 1 (isomer 2)).
- the diastereomers were separated, followed by neutralization and evaporation. Purification of the single diastereomeric compound was completed on a RP-18 column, acetonitrile/water. The corresponding fractions were pooled and the solvent was removed by distillation.
- the two products (diastereomers 755 Compound 1 (isomer 1) and 755 Compound 1 (isomer 2)) were dried in high vacuum.
- UV-vis (PBS): ⁇ max 752 nm; ⁇ em 778 nm
- DyLight 800-NHS 755 Compound 4/4-NHS MW (g/mol) 1050 1684.9 Ex (nm) 777 783 Em (nm) 794 797 ⁇ (M ⁇ 1 cm ⁇ 1 ) 270,000 270,000 (theoretical) PEG N/A 4/4 (length/number of PEG groups on compound Sulfonates 3 3
- Excitation/emission spectra of 755 Compound 4/4-NHS was within +/ ⁇ 10 nm compared to DyLight 800-NHS.
- DyLight 650 1/1 and DyLight 650 4/4 were dissolved in dimethylformamide (DMF) at 10 mg/ml, mixed on a vortex mixer for 15 seconds, and observed to determine if the dyes went into solution. The dyes were then allowed to incubate for five minutes and again mixed on a vortex mixer for 30 seconds. DyLight 650 (4/4) dissolved immediately and DyLight 650 (1/1) did not go into solution until it was incubated for five minutes and mixed again.
- DMF dimethylformamide
- Inventive and commercial compounds each as the NHS ester, were conjugated to goat anti-mouse (GAM) and goat anti-rabbit (GAR) antibodies.
- GAM and GAR at 10 mg/ml in phosphate buffered saline (PBS), were dialyzed against 50 mM borate buffer, pH 8.5.
- PBS phosphate buffered saline
- the compounds were reconstituted in DMF, and CF 647 was reconstituted in dimethylsulfoxide (DMSO), at 10 mg/ml and combined at 2.5 ⁇ , 5 ⁇ , 10 ⁇ , or 15 ⁇ molar excess with GAM or GAR for about two hours at room temperature to label the antibodies.
- DMSO dimethylsulfoxide
- Labeled compounds also termed dyes or labels, were subjected to PDDR to remove the unlabeled (free) compound; 100-200 ⁇ l of the packed resin was used per mg of protein purified.
- the purified antibody-labeled dyes were then diluted 1:50 in PBS and scanned for absorbance from 700 nm to 230 nm on a UV Cary spectrophotometer to determine the protein concentration, and to determine the mole dye to mole protein ratio.
- Each conjugate was diluted 1:10 in 50% glycerol and heated in the presence of 10 mM dithiothreitol (DTT) for 5 min at 95° C., then separated by electrophoresis on polyacrylamide gels in the presence of sodium dodecyl sulfate (SDS-PAGE). The gels were scanned using the Typhoon 9400 Imager to verify removal of the unconjugated compound. Labeling efficiency was compared, with results showing degree of labeling below, where 650 Compound 1/1 (4S) denotes four sulfo groups on the compound and 650 Compound 1/1 (2S) denotes two sulfo groups on the compound.
- DTT dithiothreitol
- SDS-PAGE sodium dodecyl sulfate
- 755 Compound 4/4 and DyLight 800 were conjugated to goat anti-mouse (GAM) and goat anti-rabbit (GAR) antibodies as described above. Briefly, 755 Compound 4/4-NHS and DyLight 800-NHS were reconstituted at 10 mg/ml in DMF. Each compound showed good solubility.
- GAM goat anti-mouse
- GAR goat anti-rabbit
- 755 Compound 4/4-NHS and DyLight 800-NHS were reconstituted at 10 mg/ml in DMF. Each compound showed good solubility.
- One mg in 100 ⁇ l of GAM or GAR was prepared at 10.0 mg/ml in borate buffer pH 8.5.
- Ten mg in 1000 ⁇ l of GAM was prepared at 10.0 mg/ml in borate buffer pH 8.5.
- Ten mg in 1000 ⁇ l of GAM was prepared at 10.0 mg/ml in PBS pH 7.4.
- GAM and GAR were labeled with each compound at 2.5 ⁇ , 5 ⁇ , 7 ⁇ (10 mg) and 9 ⁇ molar excesses.
- Ten mg GAM was labeled with each compound at 5 ⁇ and 7 ⁇ molar excesses in borate buffer.
- Ten mg GAM was labeled with each compound at 5 ⁇ and 7 ⁇ molar excesses in PBS buffer, and incubated for greater than 60 min.
- Conjugates were purified on Pierce Dye Removal Resin in Harvard columns with 100-200 ⁇ l resin per mg of each conjugate. All the conjugates were diluted 1:50 and scanned on UV Cary Spectrophotometer. Absorption maxima for free compounds is shown in FIG.
- Performance of the dye-GAM conjugates and dye-GAR conjugates was evaluated in a functional assay.
- Wells of a 96 white opaque plate were coated with target proteins mouse IgG immunoglobulin or rabbit IgG immunoglobulin.
- One hundred ⁇ l mouse or rabbit IgG at a concentration of 10 ⁇ g/ml was applied to the corresponding wells in columns 1 and 2.
- the target proteins were serially diluted 1:1 from the wells in columns 2 to 11 using 100 ⁇ l PBS.
- One hundred ⁇ l of the samples from the wells in column 11 were discarded.
- One hundred ⁇ l PBS was added to the wells in column 12.
- the plates were incubated overnight at 4° C. and then blocked 2 ⁇ 200 ⁇ l with Thermo Scientific SuperBlock® Blocking Buffer.
- the coated plates were washed 2 ⁇ 200 ⁇ l with PBS-Tween and 1 ⁇ 200 ⁇ l with PBS. Based on the calculated concentrations, GAM and GAR conjugates were diluted 1:250 (of 1 mg/ml) in PBS buffer. Conjugates diluted in PBS to 4 ⁇ g/ml were added to the corresponding plates (100 ⁇ l/well) and then incubated for 1 h in the dark. The plates were washed with 2 ⁇ 200 ⁇ l with PBS-Tween and 1 ⁇ 200 ⁇ l with PBS and filled with PBS buffer (100 ⁇ l/well) prior to scanning on Tecan Safire to detect fluorescence intensity.
- the relative fluorescence units (RFU) or signal-to-background ratio (S/B) of the dyes were compared at various concentrations, using the indicated conjugation conditions.
- FIG. 2 shows results of a functional assay using GAR conjugated with either 650 Compound 4/4 (diamonds), 650 Compound 1/1 (circles), CF 647 (triangles), or Alexa Fluor 647 (squares) at a 2.5 ⁇ molar excess of the dyes, showing relative fluorescence units (RFU) versus amount of target antibody per well (ng/well).
- FIG. 3 shows the signal-to-background ratio (SB) of the functional assay of FIG. 2 , showing either 650 Compound 4/4 (diamonds), 650 Compound 1/1 (circles), CF 647 (triangles), or Alexa Fluor 647 (squares) at a 2.5 ⁇ molar excess of the dyes.
- SB signal-to-background ratio
- FIG. 4 shows results of a functional assay using GAR conjugated with either 650 Compound 4/4 (diamonds), 650 Compound 1/1 (circles), CF 647 (triangles), or Alexa Fluor 647 (squares) at a 5 ⁇ molar excess of the dyes, showing relative fluorescence units (RFU) versus amount of target antibody per well (ng/well).
- FIG. 5 shows the signal-to-background ratio (SB) of the functional assay of FIG. 4 , showing either 650 Compound 4/4 (diamonds), 650 Compound 1/1 (circles), CF 647 (triangles), or Alexa Fluor 647 (squares) at a 5 ⁇ molar excess of the dyes.
- SB signal-to-background ratio
- 650 Compound 1/1-GAR was the best performing conjugate at all molar excesses. Up to 125 ng/well of rabbit IgG, the 650 Compound 4/4-GAR showed similar binding fluorescence as Alexa Fluor 647-GAR but better than CF 647-GAR. CF 647 showed significantly lower performance of all the conjugates.
- FIG. 6 shows results of a functional assay using GAM conjugated with either 650 Compound 4/4 (diamonds), 650 Compound 1/1 (circles), CF 647 (triangles), or Alexa Fluor 647 (squares) at a 2.5 ⁇ molar excess of the dyes, showing relative fluorescence units (RFU) versus amount of target antibody per well (ng/well).
- FIG. 7 shows the signal-to-background ratio (SB) of the functional assay of FIG. 6 , showing either 650 Compound 4/4 (diamonds), 650 Compound 1/1 (circles), CF 647 (triangles), or Alexa Fluor 647 (squares) at a 2.5 ⁇ molar excess of the dyes.
- SB signal-to-background ratio
- FIG. 8 shows results of a functional assay using GAM conjugated with either 650 Compound 4/4 (diamonds), 650 Compound 1/1 (circles), CF 647 (triangles), or Alexa Fluor 647 (squares) at a 5 ⁇ molar excess of the dyes, showing relative fluorescence units (RFU) versus amount of target antibody per well (ng/well).
- FIG. 9 shows the signal-to-background ratio (SB) of the functional assay of FIG. 8 , showing either 650 Compound 4/4 (diamonds), 650 Compound 1/1 (circles), CF 647 (triangles), or Alexa Fluor 647 (squares) at a 5 ⁇ molar excess of the dyes.
- SB signal-to-background ratio
- 650 Compound 1/1-GAM was the best performing conjugate at all molar excesses. Up to 125 ng/well of mouse IgG, 650 Compound 4/4-GAM showed similar binding fluorescence as Alexa Fluor 647-GAM but better than CF 647-GAM. CF-647 showed significantly lower performance of all the conjugates.
- FIG. 11A Average total bound fluorescence intensity is shown in FIG. 11A , with 755 Compound 4/4-GAR (solid lines) and DyLight 800-GAR (dotted lines) at either 2.5 ⁇ molar excess (triangles), 5 ⁇ molar excess (diamonds), 7 ⁇ molar excess (circles), or 9 ⁇ molar excess (squares).
- FIG. 11B shows the plate image of FIG.
- Average total unbound fluorescence intensity is shown in FIG. 12A , and corresponding plate image in FIG. 12B , showing 1 (755 Compound 4/4-GAR; 7 ⁇ molar excess; D/P 2.22), 2 (DyLight 800-GAR; 7 ⁇ molar excess; D/P 1.39), 3 (IR800-GAR (Rockland); D/P 2.6), and 4 (DyLight 800-GAR (Rockland); D/P 2.1). Average total bound fluorescence intensity is shown in FIG.
- FIG. 13A shows the plate image of FIG. 13A , showing 1 (755 Compound 4/4-GAR; 7 ⁇ molar excess), 2 (DyLight 800-GAR; 7 ⁇ molar excess), 3 (IR800-GAR (Rockland)), and 4 (DyLight 800-GAR (Rockland)).
- 755 Compound 4/4-GAR showed significantly higher binding fluorescence intensity compared to DyLight 800-GAR conjugates in borate buffer.
- 755 Compound 4/4-GAR performed better than IR800-GAR (conjugate made by Rockland using IR800 Dye from LiCOR; sold in lyophilized form) and DyLight 800-GAR (conjugate made by Rockland using DyLight 800; sold in lyophilized form). No quenching at high dye molar excesses was observed with 755 Compound 4/4.
- the inventive compounds and commercial dye were evaluated for immunofluorescence in cell based assays using the following protocol. Plates containing U2OS cells (human osteosarcoma cell line) were fixed in 4% paraformaldehyde in PBS/0.1% Triton X-100 for 15 min at room temperature. The cells were then permeabilized with 2% BSA in PBS/0.1% Triton X-100 for 15 min at room temperature. Negative controls contain only 2% BSA/PBS-0.1% Triton-X100 blocker.
- Diluted primary antibodies, mouse-anti-protein disulphide isomerase (PDI) or rabbit-anti-HDAC2, diluted in 2% BSA/PBS-0.1% Triton-X100 were added to the plates and incubated for one hour at room temperature.
- Negative controls contain only 2% BSA/PBS-0.1% Triton-X100 blocker.
- the plates were washed 3 ⁇ 100 ⁇ l with PBS. Based on the calculated protein concentrations, the conjugates made in Example 22 were diluted to 4 ⁇ g/ml in PBS/0.1% Triton X-100 and added to the plates (50 ⁇ l/well) and incubated one hour in the dark at room temperature.
- FIGS. 14A-E shows results of an immunofluorescence assay using rabbit-anti-HDAC2 as a primary antibody, and either 650 Compound 4/4-GAR ( FIG. 14A ; column A), 650 Compound 1/1 (4S)-GAR ( FIG. 14B ; column A), CF 647-GAR ( FIG. 14C ; column A), Alexa Fluor 647-GAR ( FIG. 14D ; column A), or 650 Compound 1/1 (2S)-GAR ( FIG.
- 650 Compound 4/4-GAR does not appear to quench
- 650 Compound 1/1, CF 647, and Alexa Fluor 647 conjugates showed significant quenching at high molar excesses.
- CF 647-GAR and Alexa 647-GAR conjugates showed lower intensity at all molar excesses.
- FIGS. 17A-D show immunofluorescence assay results using mouse-anti-PDI as a primary antibody, and either 650 Compound 4/4-GAR ( FIG. 17A ; column A), 650 Compound 1/1 (4S)-GAR ( FIG. 17B ; column A), CF 647-GAR ( FIG. 17C ; column A), or Alexa Fluor 647-GAR ( FIG. 17D ; column A) as secondary antibody, with negative controls shown in column B, where the compound was conjugated to GAM (secondary antibody) at 2.5 ⁇ molar excess (row 1), 5 ⁇ molar excess (row 2), 10 ⁇ molar excess (row 3), or 15 ⁇ molar excess (row 4).
- GAM secondary antibody
- 650 Compound 4/4-GAM was the brightest at all molar excesses.
- 650 Compound 1/1, CF 647, and Alexa Fluor 647 conjugates showed significant quenching above 2.5 ⁇ molar excess.
- CF 647-GAM and Alexa 647-GAM conjugates showed lower intensity at all molar excesses.
- FIGS. 17A-D Quantitative analysis of the data of FIGS. 17A-D , expressed as Mean Total Intensity, which is the average total intensity of all pixels within a defined area or defined primary object such as a nucleus, is shown in FIG. 18 and signal to background ratio (S/B) is shown in FIG. 19 , at molar excesses of 2.5 ⁇ (open bars), 5 ⁇ (upward diagonal lined bars), 10 ⁇ (downward diagonal lined bars), and 15 ⁇ (vertical lined bars).
- S/B signal to background ratio
- 650 Compound 4/4-GAM was the brightest at all molar excesses.
- 650 Compound 4/4-GAM showed quenching above 5 ⁇ molar excess, while 650 Compound 1/1, CF 647, and Alexa Fluor 647 conjugates showed significant quenching above 2.5 ⁇ molar excess. CF 647-GAM and Alexa 647-GAM conjugates showed lower intensity at all molar excesses.
- FIGS. 20A-D shows results of an immunofluorescence assay using rabbit-anti-HDAC2 as a primary antibody, and either 650 Compound 4/4-GAR ( FIG. 20A ; column A), 650 Compound 1/1 (4S)-GAR ( FIG. 20B ; column A), CF 647-GAR ( FIG. 20C ; column A), or Alexa Fluor 647-GAR ( FIG. 20D ; column A) as secondary antibody, with negative controls shown in column B, where the compound was conjugated to GAR (secondary antibody) at 2.5 ⁇ molar excess (row 1), 5 ⁇ molar excess (row 2), 10 ⁇ molar excess (row 3), or 15 ⁇ molar excess (row 4).
- GAR secondary antibody
- 650 Compound 4/4-GAR was the brightest at all molar excesses.
- 650 Compound 1/1, CF 647, and Alexa Fluor 647 conjugates showed significant quenching above 2.5 ⁇ molar excess.
- CF 647-GAR and Alexa 647-GAR conjugates showed lower intensity at all molar excesses.
- FIGS. 20A-D Quantitative analysis of the data of FIGS. 20A-D , expressed as Mean Total Intensity, which is the average total intensity of all pixels within a defined area or defined primary object such as a nucleus, is shown in FIG. 21 and signal to background ratio (S/B) is shown in FIG. 22 , at molar excesses of 2.5 ⁇ (open bars), 5 ⁇ (upward diagonal lined bars), 10 ⁇ (downward diagonal lined bars), and 15 ⁇ (vertical lined bars). 650 Compound 1/1, CF 647, and Alexa Fluor 647 conjugates showed the highest binding intensity at 2.5 ⁇ dye molar excess, however 650 Compound 4/4 was the brightest at all molar excesses.
- Mean Total Intensity which is the average total intensity of all pixels within a defined area or defined primary object such as a nucleus
- 650 Compound 4/4-GAR did not appear to quench
- 650 Compound 1/1, CF 647, and Alexa Fluor 647 conjugates showed significant quenching above 2.5 ⁇ molar excess.
- CF 647-GAR and Alexa 647-GAR conjugates showed lower intensity at all molar excesses.
- 650 Compound 4/4-NHS was within +/ ⁇ 10 nm compared to 650 Compound 1/1-NHS, Alexa Fluor 647-NHS, and CF 647-NHS ester. Labeling efficiency of 650 Compound 4/4 was the highest, followed by 650 Compound 1/1, compared to the other dyes at each molar excess. 650 Compound 1/1 and CF 647 required extra time for complete solubility. 650 Compound 1/1-GAM/R was the best performing conjugate at all molar excesses.
- 650 Compound 4/4-GAM showed similar binding fluorescence as 650 Compound 1/1-GAM and Alexa Fluor 647-GAM, but better than CF 647-GAM.
- CF 647 showed significantly lower performance of all dyes. When purified with 200 ⁇ l of resin/mg of protein, the conjugates did not show any non-specific binding. Conjugates made with 650 Compound 4/4 (GAM/R) were the brightest and showed the highest signal to background ratios.
- 650 Compound 1/1, CF 647, and Alexa Fluor 647 conjugates showed significant quenching above 2.5 ⁇ molar excess.
- CF 647 and Alexa Flour 647 conjugates showed lower intensity at all molar excesses.
- the inventive compounds are evaluated for stability. All compounds are packed under argon in plastic vials. The vials are sealed with a drying pad in an aluminium coated pouch, and then stored at 50° C. for seven days.
- inventive compounds are evaluated in direct fluorescence labeling of cell surface proteins using methods known in the art.
- suitable cell plates such as IMR90 cells (human lung embryonic fibroblast) are washed and then incubated with the conjugates.
- the cell plates are then washed and imaged using an appropriate instrument, such as a Thermo Scientific ArrayScan VTI HCS Reader.
- the inventive compounds are used for in vivo imaging to obtain information about biological tissues that are not readily accessible.
- the compounds are responsive to light in the near infrared (NIR) region of the spectrum, which is a part of the spectrum that has minimal interference from the absorbance of biological materials.
- the compounds are used for fluorescent imaging of targets within animals.
- in vivo imaging information can be obtained using methods such as X-ray, magnetic resonance imaging, positron emission tomography, ultrasound imaging and probing, and other non-invasive methods used for diagnosing and treating disease.
- Light in the NIR region from about 650 nm to about 1000 nm wavelength, can permeate through several centimeters of tissue and therefore, can be used for in vivo imaging.
- Fluorescent dyes such as the inventive compounds that are responsive to light in these longer wavelengths, can be used as conjugates with targeting molecules such as antibodies to bind and accumulate in, e.g., diseased tissue such as tumors, and may be used to distinguish healthy from diseased tissue.
- the inventive compound may be attached to a biomolecule, such as a protein, peptide, or a drug, which is localized or retained in the desired tissue environment.
- Fluorescent in vivo imaging using NIR dyes such as the inventive compounds are diagnostic agents to discretely target disease tissue directly within animals or humans.
- the compound or a conjugate of the compound with a targeting agent is administered to a tissue (e.g., intravenously), permitted to accumulate with excess compound removed by the circulatory system, then the tissue is irradiated with light at an appropriate wavelength. NIR fluorescent light is recorded and/or an image is generated from the data obtained to specifically detect and visualize the targeted cells or tissues.
- the dose of compound administered can differ depending upon the specific tissue, application, etc., as long as the method achieves a detectable concentration of the compound in the tissue to be assessed.
- the inventive dyes were evaluated in biodistribution and bioclearance studies.
- One mg NHS-DyLight 650 4/4 and NHS-DyLight 650 1/1 are reconstituted to 10 mg/ml and diluted to 1 mg/ml in PBS.
- the dyes are incubated for 30 minutes and then quenched by adding one-tenth volume of 3M N-ethanolamine.
- One hundred ⁇ L of 1 mg/mL of each hydrolyzed dye solution is intravenously injected via the retro orbital plexus of non-tumored nude mice.
- One mouse is injected for each dye.
- the animals are imaged on a Carestream MSFX at 0 h, 3 h, 6 h, 12 h, and 24 h post injection.
- 650 Compound 4/4-NHS is conjugated to a rabbit anti-HER2 antibody (Genscript USA, Piscataway N.J.) by reconstituting the compound in dimethylformamide (DMF) at 10 mg/ml, then incubated at 10 ⁇ molar excess with rabbit anti-HER2 antibody (0.1 mg) for 1 h at room temperature to result in a 650 Compound 4/4-anti-HER2 conjugate.
- the sample is then subjected to PDDR to remove unlabeled (free) 650 Compound 4/4.
- Ten microgram of the conjugate is injected intravenously (IV) to athymic mice bearing BT474 tumors. The animals are imaged overtime at 1, 24, 48, 72, 96, and 120 hours post-injection using Pearl Impulse Imager from LI-COR Biosciences (LI-COR Instruments, Lincoln Nebr.).
- fluorescence intensity is observed to be distributed over the whole animal during the first hour imagining and diminishes significantly at 72 hours. After 96 hours, the signal is localized and specific to the tumor.
- the compound may be rendered less hydrophilic, i.e., more hydrophobic or less negatively charged, by altering the number of sulfonate groups. Fewer sulfonates render the compound more hydrophobic and less negatively charged. In this embodiment, the compound may be more readily retained in a desired tissue or location if the appropriate number of sulfonates is determined. For example, compound penetration into cells is more efficient if fewer sulfonates are on the compound.
- the compound may contain one, two, three, or four sulfonate groups. Hydrophobic compounds are also known to more efficiently cross the cell membrane, and therefore are more desirable when the target of interest is located within the cell.
- Alendronate a compound that binds to, and is retained in, LNCap prostate cancer cells, is conjugated with disulfonated or monosulfonated 650 Compound 4/4 by incubating a solution containing 1 mM disulfonated or monosulfonated 650 Compound 4/4-NHS in 1 ml of PBS and 0.5 ml tetrahydrofuran (THF) with 0.1 mM alendronate and 0.2 mM diisopropylethylamine at room temperature overnight.
- THF 0.5 ml tetrahydrofuran
- the conjugate is purified using reverse phase HPLC with 0-50% methanol against a 0.1 M ammonium acetate buffer, and is then lyophilized.
- LNCap cells are grown orthotopically in nude mice.
- 650 Compound 1 (isomer 1)-alendronate (5 nmole) is injected into the tumor.
- Control mice are injected with free 650 Compound 4/4 containing a carboxylic acid residue instead of the reactive NHS ester.
- X-ray and near infra-red fluorescence images are captured.
- both the monosulfonated and disulfonated 650 Compound 4/4-alendroneate conjugate is retained in mouse tissue but the free dyes are not retained; the conjugate is retained in the LNCap cell-induced tumor for at least 18 hrs.
- a drug delivery nanoparticle system conjugated with disulfonated and monosulfonated 650 Compound 4/4 is prepared as follows. A solution containing 1 mM disulfonated or monosulfonated 650 Compound 4/4-NHS in 1 ml of PBS is incubated overnight at room temperature with 0.1 mM of an anti-cancer drug conjugated with transferrin in the form of a nanoparticle. The resulting 650 Compound 4/4-nanoparticle conjugates are purified by centrifugation, and then lyophilized.
- the 650 Compound 4/4-nanoparticle conjugates (1 nmole) are injected intravenously into the tail vein of different mice. Control mice are injected with non-reactive 650 Compound 4/4 dye containing a carboxylic acid residue instead of a reactive NHS ester. X-ray and near infra-red fluorescence images of mouse brain are captured.
- Both 650 Compound 4/4-nanoparticle conjugates are found to localize in the mouse brain for greater than about 24 hours after injection. Tumor size progressively decreases after injection of 650 Compound 4/4-nanoparticle conjugate, compared to 650 Compound 4/4-nanoparticle without the anti-cancer drug.
- the mono-sulfonated derivative could be on any one of six possible positions on the 650 compound, accounting for the stereochemistry around the carbon positions on the rings as well as the non-symmetrical nature of the two ends of each dye.
- the di- and tri-substituted sulfonates could be on multiple possible positions on the inventive compounds.
- Log P (partition coefficient) and log D (distribution coefficient) of inventive and commercial compounds were determined to assess compound hydrophilicity.
- the log P value of a compound is the logarithm of a compound's partition coefficient between n-octanol and water log(C octanol /C water ), and is a well established measure of a compound's hydrophilicity.
- Log P is a constant for the molecule under its neutral form. Low hydrophilicity, and thus high log P, causes poor absorption or permeation. For compounds to have a reasonable probability of being well absorbed, their log P is generally ⁇ 5.0.
- Lipophilicity is not determined by the partitioning of the neutral species in octanol/water, but by the distribution of both the neutral and positively charged forms of the molecule.
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Abstract
Description
where each of R1 and R2 is the same or different and is independently selected from the group consisting of an aliphatic, heteroaliphatic, sulfoalkyl, heteroaliphatic with terminal SO3, a PEG group P-L-Z where P is selected from an ethylene glycol group, a diethylene glycol group, and a (poly)ethylene glycol group where the (poly)ethylene glycol group is (CH2CH2O)s where s is an integer from 3-6 inclusive, a sulfonamide group -L-SO2NH—P-L-Z, and a carboxamide group -L-CONH—P-L-Z; where L is selected from the group consisting of a divalent linear (—(CH2)o—, o=0 to 15), crossed, or cyclic alkane group that can be substituted by at least one atom selected from the group consisting of oxygen, substituted nitrogen, and/or sulfur; where Z is selected from the group consisting of H, CH3, alkyl, heteroalkyl, NH2, —COO−, —COOH, —COSH, CO—NH—NH2, —COF, —COCl, —COBr, —COI, —COO-Su (succinimidyl/sulfo-succinimidyl), —COO-STP (4-sulfo-2,3,5,6-tetrafluorophenyl), —COO-TFP (2,3,5,6-tetrafluorophenyl), —COO-benzotriazole, —CO-benzotriazole, —CONR′—CO—CH2—I, —CONR′R″, —CONR′— biomolecule, —CONR′-L-COO, —CONR′-L-COOH, —CONR′-L-COO-Su, —CONR′-L-COO-STP, —CONR′-L-COO-TFP, —CONR′-L-CONR″2, —CONR′-L-CO-biomolecule, —CONR′-L-CO—NH—NH2, —CONR′-L-OH, —CONR′-L-O-phosphoramidite, —CONR′-L-CHO, —CONR′-L-maleimide, and —CONR′-L-NH—CO—CH2—I; R′ and R″ is selected from the group consisting of H, aliphatic group, and heteroaliphatic group, and the biomolecule is a protein, antibody, nucleotide, oligonucleotide, biotin, or hapten; X is selected from the group consisting of —OH, —SH, —NH2, —NH—NH2, —F, —Cl, —Br, I, —NHS (hydroxysuccinimidyl/sulfosuccinimidyl), —O-TFP (2,3,5,6-tetrafluorophenoxy), —O-STP (4-sulfo-2,3,5,6-tetrafluorophenoxy), —O-benzotriazole, -benzotriazole, —NR-L-OH, —NR-L-O-phosphoramidite, —NR-L-SH, —NR-L-NH2, —NR-L-NH—NH2, —NR-L-CO2H, —NR-L-CO—NHS, —NR-L-CO-STP, —NR-L-CO-TFP, —NR-L-CO-benzotriazole, —NR-L-CHO, —NR-L-maleimide, and —NR-L-NH—CO—CH2-I, where R is —H or an aliphatic or heteroaliphatic group; Kat is a number of Na+, K+, Ca2+, ammonia, or other cation(s) needed to compensate the negative charge brought by the cyanine; m is an integer from 0 to 5 inclusive; o is an integer from 0 to 12 inclusive; and n is an integer from 1 to 3 inclusive; with the proviso that at least one of R1 and R2 contains a PEG group.
is provided, where each of R1 and R2 is the same or different and is independently selected from the group consisting of aliphatic, heteroaliphatic, sulfoalkyl, heteroaliphatic with terminal SO3, a PEG group P-L-Z where P is selected from an ethylene glycol group, a diethylene glycol group, and a (poly)ethylene glycol group where the (poly)ethylene glycol group is (CH2CH2O)s where s is an integer from 3-6 inclusive, a sulfonamide group -L-SO2NH—P-L-Z, and a carboxamide group -L-CONH—P-L-Z; where L is selected from the group consisting of a divalent linear (—(CH2)o—, o=0 to 15), crossed, or cyclic alkane group that can be substituted by at least one atom selected from the group consisting of oxygen, substituted nitrogen, and/or sulfur; where Z is selected from the group consisting of H, CH3, alkyl, heteroalkyl, NH2, —COO, —COOH, —COSH, CO—NH—NH2, —COF, —COCl, —COBr, —COI, —COO-Su (succinimidyl/sulfosuccinimidyl), —COO-STP (4-sulfo-2,3,5,6-tetrafluorophenyl), —COO-TFP (2,3,5,6-tetrafluorophenyl), —COO-benzotriazole, —CO-benzotriazole, —CONR′—CO—CH2—I, —CONR′R″, —CONR′-biomolecule, —CONR′-L-COO, —CONR′-L-COOH, —CONR′-L-COO-Su, —CONR′-L-COO-STP, —CONR′-L-COO-TFP, —CONR′-L-CONR″2, —CONR′-L-CO-biomolecule, —CONR′-L-CO—NH—NH2, —CONR′-L-OH, —CONR′-L-O-phosphoramidite, —CONR′-L-CHO, —CONR′-L-maleimide, and —CONR′-L-NH—CO—CH2—I; R′ and R″ is selected from the group consisting of —H, aliphatic, and heteroaliphatic, and the biomolecule is a protein, antibody, nucleotide, oligonucleotide, biotin, or hapten; X is selected from the group consisting of —OH, —SH, —NH2, —NH—NH2, —F, —Cl, —Br, I, —NHS (hydroxysuccinimidyl/sulfo-succinimidyl), —O-TFP (2,3,5,6-tetrafluorophenoxy), —O-STP (4-sulfo-2,3,5,6-tetrafluorophenoxy), —O-benzotriazole, -benzotriazole, —NR-L-OH, —NR-L-O-phosphoramidite, —NR-L-SH, —NR-L-NH2, —NR-L-NH—NH2, —NR-L-CO2H, —NR-L-CO—NHS, —NR-L-CO-STP, —NR-L-CO-TFP, —NR-L-CO-benzotriazole, —NR-L-CHO, —NR-L-maleimide, and —NR-L-NH—CO—CH2-I, where R is —H or an aliphatic or heteroaliphatic group; Kat is a number of Na+, K+, Ca2+, ammonia, or other cation(s) needed to compensate the negative charge brought by the cyanine; m is an integer from 0 to 5 inclusive; o is an integer from 0 to 12 inclusive; and n is an integer from 1 to 3 inclusive; with the proviso that at least one of R1 and R2 contains a PEG group.
where each of R1, R2, R5, and R6 is the same or different and is independently selected from the group consisting of aliphatic, heteroaliphatic, sulfoalkyl, heteroaliphatic with terminal SO3, a PEG group P-L-Z where P is selected from an ethylene glycol group, a diethylene glycol group, and a (poly)ethylene glycol group where the (poly)ethylene glycol group is (CH2CH2O)s where s is an integer from 3-6 inclusive, a sulfonamide group -L-SO2NH—P-L-Z, and a carboxamide group -L-CONH—P-L-Z; each of R7 and R8 is the same or different and is independently selected from the group consisting of H, SO3, a PEG group P-L-Z where P is selected from an ethylene glycol group, a diethylene glycol group, and a (poly)ethylene glycol group where the (poly)ethylene glycol group is (CH2CH2O)s where s is an integer from 3-6 inclusive, a sulfonamide group —SO2NH—P-L-Z, and a carboxamide group —CONH—P-L-Z; where L is selected from the group consisting of a divalent linear (—(CH2)o—, o=0 to 15), crossed, or cyclic alkane group that can be substituted by at least one atom selected from the group consisting of oxygen, substituted nitrogen, and/or sulfur; where Z is selected from the group consisting of H, CH3, alkyl, heteroalkyl, NH2, —COO, —COOH, —COSH, CO—NH—NH2, —COF, —COCl, —COBr, —COI, —COO-Su (succinimidyl/sulfosuccinimidyl), —COO-STP (4-sulfo-2,3,5,6-tetrafluorophenyl), —COO-TFP (2,3,5,6-tetrafluorophenyl), —COO-benzotriazole, —CO-benzotriazole, —CONR′—CO—CH2—I, —CONR′R″, —CONR′-biomolecule, —CONR′-L-COO, —CONR′-L-COOH, —CONR′-L-COO-Su, —CONR′-L-COO-STP, —CONR′-L-COO-TFP, —CONR′-L-CONR″2, —CONR′-L-CO-biomolecule, —CONR′-L-CO—NH—NH2, —CONR′-L-OH, —CONR′-L-O-phosphoramidite, —CONR′-L-CHO, —CONR′-L-maleimide, and —CONR′-L-NH—CO—CH2—I; R′ and R″ is selected from the group consisting of H, aliphatic group, and heteroaliphatic group, and the biomolecule is a protein, antibody, nucleotide, oligonucleotide, biotin, or hapten; X is selected from the group consisting of —OH, —SH, —NH2, —NH—NH2, —F, —Cl, —Br, I, —NHS (hydroxysuccinimidyl/sulfo-succinimidyl), —O-TFP (2,3,5,6-tetrafluorophenoxy), —O-STP (4-sulfo-2,3,5,6-tetrafluorophenoxy), —O-benzotriazole, -benzotriazole, —NR-L-OH, —NR-L-O-phosphoramidite, —NR-L-SH, —NR-L-NH2, —NR-L-NH—NH2, —NR-L-CO2H, —NR-L-CO—NHS, —NR-L-CO-STP, —NR-L-CO-TFP, —NR-L-CO-benzotriazole, —NR-L-CHO, —NR-L-maleimide, and —NR-L-NH—CO—CH2—I, where R is —H or an aliphatic or heteroaliphatic group; Kat is a number of Na+, K+, Ca2+, ammonia, or other cation(s) needed to compensate the negative charge brought by the cyanine; m is an integer from 0 to 5 inclusive; o is an integer from 0 to 12 inclusive; and n is an integer from 1 to 3 inclusive; with the proviso that at least one of R1, R2, R5, R6, R7, and R8 contains a PEG group.
where each of R1, R2, R5, and R6 is the same or different and is independently selected from the group consisting of an aliphatic, heteroaliphatic, sulfoalkyl group, heteroaliphatic with terminal SO3, a PEG group P-L-Z where P is selected from an ethylene glycol group, a diethylene glycol group, and a (poly)ethylene glycol group where the (poly)ethylene glycol group is (CH2CH2O)s where s is an integer from 3-6 inclusive, a sulfonamide group -L-SO2NH—P-L-Z, and a carboxamide group -L-CONH—P-L-Z; each of R7 and R8 is the same or different and is independently selected from the group consisting of H, SO3, a PEG group P-L-Z where P is selected from an ethylene glycol group, a diethylene glycol group, and a (poly)ethylene glycol group where the (poly)ethylene glycol group is (CH2CH2O)s where s is an integer from 3-6 inclusive, a sulfonamide group —SO2NH—P-L-Z, and a carboxamide group —CONH—P-L-Z; where L is selected from the group consisting of a divalent linear (—(CH2)o—, o=0 to 15), crossed, or cyclic alkane group that can be substituted by at least one atom selected from the group consisting of oxygen, substituted nitrogen, and/or sulfur; where Z is selected from the group consisting of H, CH3, alkyl, heteroalkyl, NH2, —COO−, —COOH, —COSH, CO—NH—NH2, —COF, —COCl, —COBr, —COI, —COO-Su (succinimidyl/sulfosuccinimidyl), —COO-STP (4-sulfo-2,3,5,6-tetrafluorophenyl), —COO-TFP (2,3,5,6-tetrafluorophenyl), —COO-benzotriazole, —CO-benzotriazole, —CONR′—CO—CH2—I, —CONR′R″, —CONR′-biomolecule, —CONR′-L-COO, —CONR′-L-COOH, —CONR′-L-COO-Su, —CONR′-L-COO-STP, —CONR′-L-COO-TFP, —CONR′-L-CONR″2, —CONR′-L-CO-biomolecule, —CONR′-L-CO—NH—NH2, —CONR′-L-OH, —CONR′-L-O-phosphoramidite, —CONR′-L-CHO, —CONR′-L-maleimide, and —CONR′-L-NH—CO—CH2—I; R′ and R″ is selected from the group consisting of H, aliphatic group, and heteroaliphatic group, and the biomolecule is a protein, antibody, nucleotide, oligonucleotide, biotin, or hapten; X is selected from the group consisting of —OH, —SH, —NH2, —NH—NH2, —F, —Cl, —Br, I, —NHS (hydroxysuccinimidyl/sulfosuccinimidyl), —O-TFP (2,3,5,6-tetrafluorophenoxy), —O-STP (4-sulfo-2,3,5,6-tetrafluorophenoxy), —O-benzotriazole, -benzotriazole, —NR-L-OH, —NR-L-O-phosphoramidite, —NR-L-SH, —NR-L-NH2, —NR-L-NH—NH2, —NR-L-CO2H, —NR-L-CO—NHS, —NR-L-CO-STP, —NR-L-CO-TFP, —NR-L-CO-benzotriazole, —NR-L-CHO, —NR-L-maleimide, and —NR-L-NH—CO—CH2-I, where R is —H or an aliphatic or heteroaliphatic group; Kat is a number of Na+, K+, Ca2+, ammonia, or other cation(s) needed to compensate the negative charge brought by the cyanine; m is an integer from 0 to 5 inclusive; p is an integer from 1 to 6 inclusive; and n is an integer from 1 to 3 inclusive; and at least one of R1, R2, R5, R6, R7, and R8 contains a PEG group.
One non-limiting example of a NHS-ester of 550 Compound 1/3, according to general formula III, where m=1 and p=1, is shown below:
One non-limiting example of a NHS-ester of 550 Compound 1/3, according to general formula III, where m=1 and p=2, is shown below:
One non-limiting example of a NHS-ester of 550
One non-limiting example of a NHS-ester of 550 Compound 1/3, according to general formula III, where m=1 and p=4, is shown below:
One non-limiting example of a NHS-ester of 550 Compound 1/3, according to general formula III, where m=1 and p=5, is shown below:
One non-limiting example of a NHS-ester of 550 Compound 1/3, according to general formula III, where m=1 and p=6, is shown below:
One non-limiting example of a NHS-ester of 550 Compound 2/3, according to general formula III, where m=2 and p=1, is shown below:
One non-limiting example of a NHS-ester of 550 Compound 2/3, according to general formula III, where m=2 and p=2, is shown below:
One non-limiting example of a NHS-ester of 550 Compound 2/3, according to general formula III, where m=2 and p=3, is shown below:
One non-limiting example of a NHS-ester of 550 Compound 3/3, according to general formula III, where m=3 and p=1, is shown below:
One non-limiting example of a NHS-ester of 550
One non-limiting example of a NHS-ester of 550 Compound 3/3, according to general formula III, where m=3 and p=3, is shown below:
One non-limiting example of a NHS-ester of 550 Compound 4/3, according to general formula III, where m=4 and p=1, is shown below:
One non-limiting example of a NHS-ester of 550 Compound 5/3, according to general formula III, where m=5 and p=1, is shown below:
One non-limiting example of a NHS-ester of 550 Compound 6/3, according to general formula III, where m=6 and p=1, is shown below:
One non-limiting example of an activated 550 Compound 1/2 is a tetrafluorophenyl (TFP)-ester form of 550 Compound 1, shown below:
One non-limiting example of an activated 550 Compound 1/2 is a sulfotetrafluorophenyl (STP)-ester form of 550 Compound 1, shown below:
One non-limiting example of an activated 550 Compound 1/2 is a maleimide form of 550 Compound 1, shown below:
The methyl group on the ethylene glycol prevents the terminal —OH from oxidation. Oxidation is known to occur, over time, on an unprotected PEG terminus. Adding a methyl ether provides this protection, and prevents reaction with electrophilic reactive groups. For functional assays, 550
The methyl group on the ethylene glycol prevents the terminal —OH from oxidation. Oxidation is known to occur, over time, on an unprotected PEG terminus. Adding a methyl ether provides this protection, and prevents reaction with electrophilic reactive groups. For functional assays, 550
The methyl group on the ethylene glycol prevents the terminal —OH from oxidation. Oxidation is known to occur, over time, on an unprotected PEG terminus. Adding a methyl ether provides this protection, and prevents reaction with electrophilic reactive groups. For functional assays, 550
The methyl group on the ethylene glycol prevents the terminal —OH from oxidation. Oxidation is known to occur, over time, on an unprotected PEG terminus. Adding a methyl ether provides this protection, and prevents reaction with electrophilic reactive groups. For functional assays, 550
The methyl group on the ethylene glycol prevents the terminal —OH from oxidation. Oxidation is known to occur, over time, on an unprotected PEG terminus. Adding a methyl ether provides this protection, and prevents reaction with electrophilic reactive groups. For functional assays, 550
general formula IVb with “b” indicating an ethylene glycol, diethylene glycol, or (poly)ethylene glycol group on the left indole N, and the chain on the right indole N terminating in COH:
general formula IVc with “c” indicating an ethylene glycol, diethylene glycol, or (poly)ethylene glycol group on the left and right indole N, and the chain on the right indole N terminating in COX:
or general formula IVd with “d” indicating an ethylene glycol, diethylene glycol, or (poly)ethylene glycol group on the left indole N, and the chain on the right indole N terminating in COH:
where each of R1, R2, R5, and R6 is the same or different and is independently selected from the group consisting of an aliphatic, heteroaliphatic, sulfoalkyl, heteroaliphatic with terminal SO3, a PEG group P-L-Z where P is selected from an ethylene glycol group, a diethylene glycol group, and a (poly)ethylene glycol group where the (poly)ethylene glycol group is (CH2CH2O)s where s is an integer from 3-6 inclusive, a sulfonamide group -L-SO2NH—P-L-Z, and a carboxamide group -L-CONH—P-L-Z; each of R7 and R8 is the same or different and is independently selected from either H, SO3, a PEG group P-L-Z where P is selected from an ethylene glycol group, a diethylene glycol group, and a (poly)ethylene glycol group, where the (poly)ethylene glycol group is (CH2CH2O)s, where s is an integer from 3-6 inclusive, a sulfonamide group —SO2NH—P-L-Z, or a carboxamide group —CONH—P-L-Z; where L is selected from the group consisting of a divalent linear (—(CH2)o—, o=0 to 15), crossed, or cyclic alkane group that can be substituted by at least one atom selected from the group consisting of oxygen, substituted nitrogen, and/or sulfur; where Z is selected from the group consisting of H, CH3, alkyl, a heteroalkyl group, NH2, —COO, —COOH, —COSH, CO—NH—NH2, —COF, —COCl, —COBr, —COI, —COO-Su (succinimidyl/sulfosuccinimidyl), —COO-STP (4-sulfo-2,3,5,6-tetrafluorophenyl), —COO-TFP (2,3,5,6-tetrafluorophenyl), —COO-benzotriazole, —CO-benzotriazole, —CONR′—CO—CH2—I, —CONR′R″, —CONR′-biomolecule, —CONR′-L-COO, —CONR′-L-COOH, —CONR′-L-COO-Su, —CONR′-L-COO-STP, —CONR′-L-COO-TFP, —CONR′-L-CONR″2, —CONR′-L-CO-biomolecule, —CONR′-L-CO—NH—NH2, —CONR′-L-OH, —CONR′-L-O-phosphoramidite, —CONR′-L-CHO, —CONR′-L-maleimide, and —CONR′-L-NH—CO—CH2—I; R′ and R″ is selected from the group consisting of H, aliphatic group, and heteroaliphatic group, and the biomolecule is a protein, antibody, nucleotide, oligonucleotide, biotin, or hapten; X is selected from the group consisting of —OH, —SH, —NH2, —NH—NH2, —F, —Cl, —Br, I, —NHS hydroxysuccinimidyl/sulfosuccinimidyl), —O-TFP (2,3,5,6-tetrafluorophenoxy), —O-STP (4-sulfo-2,3,5,6-tetrafluorophenoxy), —O-benzotriazole, -benzotriazole, —NR-L-OH, —NR-L-O-phosphoramidite, —NR-L-SH, —NR-L-NH2, —NR-L-NH—NH2, —NR-L-CO2H, —NR-L-CO—NHS, —NR-L-CO-STP, —NR-L-CO-TFP, —NR-L-CO-benzotriazole, —NR-L-CHO, —NR-L-maleimide, and —NR-L-NH—CO—CH2-I, where R is —H or an aliphatic or heteroaliphatic group; Kat is a number of Na+, K+, Ca2+, ammonia, or other cation(s) needed to compensate the negative charge brought by the cyanine; m is an integer from 0 to 5 inclusive; p is an integer from 1 to 6 inclusive; each of R3 and R4 is the same or different and is independently hydrogen, an aliphatic group, a heteroaliphatic group, or a PEG group P-L-Z where P is selected from an ethylene glycol group, a diethylene glycol group, and a (poly)ethylene glycol group where the (poly)ethylene glycol group is (CH2CH2O)s where s is an integer from 3-6 inclusive; or R3 and R4 together form a cyclic structure where R3 and R4 are joined using a divalent structural element selected from the group consisting of —(CH2)q—, —(CH2)qO(CH2)q′—, —(CH2)qS(CH2)q′—, —(CH2)qCH═CH—, —OCH═CH— where each of q and q′ is the same or different and is a integer from 2 to 6 inclusive; and Y is selected from the group consisting of hydrogen, alkyl, sulfoalkyl, fluorine, chlorine, bromine, a substituted or unsubstituted aryl-, phenoxy- or phenylmercapto function; and Y is selected from the group consisting of hydrogen, alkyl, sulfoalkyl, fluorine, chlorine, bromine, and a PEG group P-L-Z where P is selected from an ethylene glycol group, a diethylene glycol group, and a (poly)ethylene glycol group where the (poly)ethylene glycol group is (CH2CH2O)s where s is an integer from 3-6 inclusive; with the proviso that at least one of R1, R2, R3, R4, R5, R6, R7, and R8 contains a PEG group.
One non-limiting example of an additionally PEG-substituted compound is a 550 Compound 1/2 according to general formula II where R1 is a diethylene glycol group terminating with a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 550 Compound 1/2 according to general formula II where R1 is a (poly)ethylene glycol (3) group terminating with a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 550 Compound 1/2 according to general formula II where R1 is a (poly)ethylene glycol (4) group terminating with a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 550 Compound 1/2 according to general formula II where R1 is a (poly)ethylene glycol (5) group terminating with a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 550 Compound 1/2 according to general formula II where R1 is a (poly)ethylene glycol (6) group terminating with a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 550 Compound 1/2 according to general formula II where R1 is a sulfonamide group -L-SO2NH—P—Z where Z is a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 550 Compound 1/2 according to general formula II where R1 is a carboxamide group -L-CONH—P—Z where Z is a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 550 Compound 1/2 according to general formula II where R2 is an ethylene glycol group terminating with a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 550 Compound 1/2 according to general formula II where R2 is a diethylene glycol group terminating with a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 550 Compound 1/2 according to general formula II where R2 is a (poly)ethylene glycol (3) group terminating with a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 550 Compound 1/2 according to general formula II where R2 is a (poly)ethylene glycol (4) group terminating with a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 550 Compound 1/2 according to general formula II where R2 is a (poly)ethylene glycol (5) group terminating with a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 550 Compound 1/2 according to general formula II where R2 is a (poly)ethylene glycol (6) group terminating with a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 550 Compound 1/2 according to general formula II where R2 is a sulfonamide group -L-SO2NH—P—Z where Z is a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 550 Compound 1/2 according to general formula II where R2 is a carboxamide group -L-CONH—P—Z where Z is a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 550 Compound 1/3 according to general formula II where both R1 and R2 are an ethylene glycol group terminating with a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 550 Compound 1/3 according to general formula II where both R1 and R2 are a diethylene glycol group terminating with a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 550 Compound 1/3 according to general formula II where both R1 and R2 are a (poly)ethylene glycol (3) group terminating with a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 550 Compound 1/3 according to general formula II where both R1 and R2 are a (poly)ethylene glycol (4) group terminating with a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 550 Compound 4/4 according to general formula III where both R1 and R2 are a (poly)ethylene glycol (4) group terminating with a methyl group, and R7 and R8 are sulfo, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 550 Compound 4/4 according to general formula III where both R1 and R2 are a (poly)ethylene glycol (4) group terminating with a methyl group, and R7 and R8 are H, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 550 Compound 1/3 according to general formula II where both R1 and R2 are a (poly)ethylene glycol (5) group terminating with a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 550 Compound 1/3 according to general formula II where both R1 and R2 are a (poly)ethylene glycol (6) group terminating with a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 550 Compound 1/2 according to general formula II where R8 is an ethylene glycol group terminating with a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 550 Compound 1/2 according to general formula II where R8 is sulfonamide —SO2NH—P—Z where Z is a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 550 Compound 1/2 according to general formula II where R8 is carboxamide —CONH—P—Z where Z is a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 550 Compound 1/2 according to general formula II where R7 is an ethylene glycol group terminating with a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 550 Compound 1/2 according to general formula II where R7 is a sulfonamide group —SO2NH—P—Z where Z is a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 550 Compound 1/2 according to general formula II where R7 is a carboxamide group —CONH—P—Z where Z is a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 550 Compound 1/3 according to general formula II where both R7 and R8 are an ethylene glycol group terminating with a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 550 Compound 1/3 according to general formula II where both R7 and R8 are a sulfonamide group —SO2NH—P—Z where Z is a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 550 Compound 1/3 according to general formula II where both R7 and R8 are a carboxamide group —CONH—P—Z where Z is a methyl group, shown below:
In one embodiment, the compound is a NHS-ester of 650 Compound 1/2 where, according to general formula I, o is 1, shown below:
One non-limiting example of a NHS-ester of 650 Compound 1/3, according to formula III, where m=1 and p=1, is shown below:
One non-limiting example of a NHS-ester of 650 Compound 1/3, according to general formula III, where m=1 and p=2, is shown below:
One non-limiting example of a NHS-ester of 650 Compound 1/3, according to general formula III, where m=1 and p=3, is shown below:
One non-limiting example of a NHS-ester of 650 Compound 1/3, according to general formula III, where m=1 and p=4, is shown below:
One non-limiting example of a NHS-ester of 650 Compound 1/3, according to general formula III, where m=1 and p=5, is shown below:
One non-limiting example of a NHS-ester of 650 Compound 1/3, according to general formula III, where m=1 and p=6, is shown below:
One non-limiting example of a NHS-ester of 650 Compound 2/3, according to general formula III, where m=2 and p=1, is shown below:
One non-limiting example of a NHS-ester of 650 Compound 2/3, according to general formula III, where m=2 and p=2, is shown below:
One non-limiting example of a NHS-ester of 650 Compound 2/3, according to general formula III, where m=2 and p=3, is shown below:
One non-limiting example of a NHS-ester of 650 Compound 3/3, according to general formula III, where m=3 and p=1, is shown below:
One non-limiting example of a NHS-ester of 650 Compound 3/3, according to general formula III, where m=3 and p=2, is shown below:
One non-limiting example of a NHS-ester of 650 Compound 3/3, according to general formula III, where m=3 and p=3, is shown below:
One non-limiting example of a NHS-ester of 650 Compound 4/3, according to general formula III, where m=4 and p=1, is shown below:
One non-limiting example of a NHS-ester of 650 Compound 5/3, according to general formula III, where m=5 and p=1, is shown below:
One non-limiting example of a NHS-ester of 650 Compound 6/3, according to general formula III, where m=6 and p=1, is shown below:
One non-limiting example of an activated 650 Compound 1/2 is the tetrafluorophenyl (TFP)-ester of 650 Compound 1/2, shown below:
One non-limiting example of an activated 650 Compound 1/2 is the sulfotetrafluorophenyl (STP)-ester of 650 Compound 1/2, shown below:
One non-limiting example of an activated 650 Compound 1/2 is the hydrazide of 650 Compound 1, shown below:
One non-limiting example of an activated 650 Compound 1/2 is the maleimide of 650 Compound 1, shown below:
where each of R1, R2, R5, and R6 is the same or different and is independently selected from the group consisting of an aliphatic, heteroaliphatic, sulfoalkyl group, heteroaliphatic with terminal SO3, a PEG group P-L-Z where P is selected from an ethylene glycol group, a diethylene glycol group, and a (poly)ethylene glycol group, where the (poly)ethylene glycol group is (CH2CH2O)s, where s is an integer from 3-6 inclusive, a sulfonamide group -L-SO2NH—P-L-Z, and a carboxamide group -L-CONH—P-L-Z; each of R7 and R8 is the same or different and is independently selected from either H, SO3, a PEG group P-L-Z where P is selected from an ethylene glycol group, a diethylene glycol group, and a (poly)ethylene glycol group where the (poly)ethylene glycol group is (CH2CH2O)s where s is an integer from 3-6 inclusive, a sulfonamide group —SO2NH—P-L-Z, or a carboxamide group —CONH—P-L-Z; where L is selected from the group consisting of a divalent linear (—(CH2)o—, o=0 to 15), crossed, or cyclic alkane group that can be substituted by at least one atom selected from the group consisting of oxygen, substituted nitrogen, and/or sulfur; where Z is selected from the group consisting of H, CH3, alkyl, a heteroalkyl group, NH2, —COO, —COOH, —COSH, CO—NH—NH2, —COF, —COCl, —COBr, —COI, —COO-Su (succinimidyl/sulfosuccinimidyl), —COO-STP (4-sulfo-2,3,5,6-tetrafluorophenyl), —COO-TFP (2,3,5,6-tetrafluorophenyl), —COO-benzotriazole, —CO-benzotriazole, —CONR′—CO—CH2—I, —CONR′R″, —CONR′-biomolecule, —CONR′-L-COO−, —CONR′-L-COOH, —CONR′-L-COO-Su, —CONR′-L-COO-STP, —CONR′-L-COO-TFP, —CONR′-L-CONR″2, —CONR′-L-CO-biomolecule, —CONR′-L-CO—NH—NH2, —CONR′-L-OH, —CONR′-L-O-phosphoramidite, —CONR′-L-CHO, —CONR′-L-maleimide, and —CONR′-L-NH—CO—CH2—I; R′ and R″ is selected from the group consisting of H, aliphatic group, and heteroaliphatic group, and the biomolecule is a protein, antibody, nucleotide, oligonucleotide, biotin, or hapten; X is selected from the group consisting of —OH, —SH, —NH2, —NH—NH2, —F, —Cl, —Br, I, —NHS (hydroxysuccinimidyl/sulfosuccinimidyl), —O-TFP (2,3,5,6-tetrafluorophenoxy), —O-STP (4-sulfo-2,3,5,6-tetrafluorophenoxy), —O-benzotriazole, -benzotriazole, —NR-L-OH, —NR-L-O-phosphoramidite, —NR-L-SH, —NR-L-NH2, —NR-L-NH—NH2, —NR-L-CO2H, —NR-L-CO—NHS, —NR-L-CO-STP, —NR-L-CO-TFP, —NR-L-CO-benzotriazole, —NR-L-CHO, —NR-L-maleimide, and —NR-L-NH—CO—CH2-I, where R is —H or an aliphatic or heteroaliphatic group; Kat is a number of Na+, K+, Ca2+, ammonia, or other cation(s) needed to compensate the negative charge brought by the cyanine; m is an integer from 0 to 5 inclusive; p is an integer from 1 to 6 inclusive; each of R3 and R4 is the same or different and is independently hydrogen, an aliphatic group, a heteroaliphatic group, or a PEG group P-L-Z where P is selected from an ethylene glycol group, a diethylene glycol group, and a (poly)ethylene glycol group, where the (poly)ethylene glycol group is (CH2CH2O)s, where s is an integer from 3-6 inclusive; or R3 and R4 together form a cyclic structure where R3 and R4 are joined using a divalent structural element selected from the group consisting of —(CH2)q—, —(CH2)qO(CH2)q′—, —(CH2)qS(CH2)q′—, —(CH2)qCH═CH—, —OCH═CH— where each of q and q′ is the same or different and is a integer from 2 to 6 inclusive; and Y is selected from the group consisting of hydrogen, alkyl, sulfoalkyl, fluorine, chlorine, bromine, and a PEG group P-L-Z where P is selected from an ethylene glycol group, a diethylene glycol group, and a (poly)ethylene glycol group, where the (poly)ethylene glycol group is (CH2CH2O)s, where s is an integer from 3-6 inclusive; with the proviso that at least one of R1, R2, R3, R4, R5, R6, R7, and R8 contains a PEG group.
is provided, where each of R1, R2, R5, and R6 is the same or different and is independently selected from the group consisting of an aliphatic, heteroaliphatic, sulfoalkyl group, heteroaliphatic with terminal SO3, a PEG group P-L-Z where P is selected from an ethylene glycol group, a diethylene glycol group, and a (poly)ethylene glycol group, where the (poly)ethylene glycol group is (CH2CH2O)s, where s is an integer from 3-6 inclusive, a sulfonamide group -L-SO2NH—P-L-Z, and a carboxamide group -L-CONH—P-L-Z; each of R7 and R8 is the same or different and is independently selected from either H, SO3, a PEG group P-L-Z where P is selected from an ethylene glycol group, a diethylene glycol group, and a (poly)ethylene glycol group where the (poly)ethylene glycol group is (CH2CH2O)s where s is an integer from 3-6 inclusive, a sulfonamide group —SO2NH—P-L-Z, or a carboxamide group —CONH—P-L-Z; where L is selected from the group consisting of a divalent linear (—(CH2)o—, o=0 to 15), crossed, or cyclic alkane group that can be substituted by at least one atom selected from the group consisting of oxygen, substituted nitrogen, and/or sulfur; where Z is selected from the group consisting of H, CH3, alkyl, a heteroalkyl group, NH2, —COO−, —COOH, —COSH, CO—NH—NH2, —COF, —COCl, —COBr, —COI, —COO-Su (succinimidyl/sulfosuccinimidyl), —COO-STP (4-sulfo-2,3,5,6-tetrafluorophenyl), —COO-TFP (2,3,5,6-tetrafluorophenyl), —COO-benzotriazole, —CO-benzotriazole, —CONR′—CO—CH2—I, —CONR′R″, —CONR′-biomolecule, —CONR′-L-COO−, —CONR′-L-COOH, —CONR′-L-COO-Su, —CONR′-L-COO-STP, —CONR′-L-COO-TFP, —CONR′-L-CONR″2, —CONR′-L-CO-biomolecule, —CONR′-L-CO—NH—NH2, —CONR′-L-OH, —CONR′-L-O-phosphoramidite, —CONR′-L-CHO, —CONR′-L-maleimide, and —CONR′-L-NH—CO—CH2-l; R′ and R″ is selected from the group consisting of H, aliphatic group, and heteroaliphatic group, and the biomolecule is a protein, antibody, nucleotide, oligonucleotide, biotin, or hapten; X is selected from the group consisting of —OH, —SH, —NH2, —NH—NH2, —F, —Cl, —Br, I, —NHS (hydroxysuccinimidyl/sulfosuccinimidyl), —O-TFP (2,3,5,6-tetrafluorophenoxy), —O-STP (4-sulfo-2,3,5,6-tetrafluorophenoxy), —O-benzotriazole, -benzotriazole, —NR-L-OH, —NR-L-O-phosphoramidite, —NR-L-SH, —NR-L-NH2, —NR-L-NH—NH2, —NR-L-CO2H, —NR-L-CO—NHS, —NR-L-CO-STP, —NR-L-CO-TFP, —NR-L-CO-benzotriazole, —NR-L-CHO, —NR-L-maleimide, and —NR-L-NH—CO—CH2-I, where R is —H or an aliphatic or heteroaliphatic group; Kat is a number of Na+, K+, Ca2+, ammonia, or other cation(s) needed to compensate the negative charge brought by the cyanine; m is an integer from 0 to 5 inclusive; o is an integer from 0 to 12 inclusive; each of R3 and R4 is the same or different and is independently hydrogen, an aliphatic group, a heteroaliphatic group, or a PEG group P-L-Z where P is selected from an ethylene glycol group, a diethylene glycol group, and a (poly)ethylene glycol group, where the (poly)ethylene glycol group is (CH2CH2O)s, where s is an integer from 3-6 inclusive; or R3 and R4 together form a cyclic structure where R3 and R4 are joined using a divalent structural element selected from the group consisting of —(CH2)q—, —(CH2)qO(CH2)q′—, —(CH2)qS(CH2)q′—, —(CH2)qCH═CH—, —OCH═CH— where each of q and q′ is the same or different and is a integer from 2 to 6 inclusive; and Y is selected from the group consisting of hydrogen, alkyl, sulfoalkyl, fluorine, chlorine, bromine, and a PEG group P-L-Z where P is selected from an ethylene glycol group, a diethylene glycol group, and a (poly)ethylene glycol group, where the (poly)ethylene glycol group is (CH2CH2O)s, where s is an integer from 3-6 inclusive; with the proviso that at least one of R1, R2, R3, and R4 contains a PEG group.
One non-limiting example of an additionally PEG-substituted compound is a 650 Compound 1/2 according to general formula II where R1 is a diethylene glycol group terminating with a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 650
One non-limiting example of an additionally PEG-substituted compound is a 650 Compound 1/2 according to general formula II where R1 is a (poly)ethylene glycol (4) group terminating with a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 650 Compound 1/2 according to general formula II where R1 is a (poly)ethylene glycol (5) group terminating with a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 650 Compound 1/2 according to general formula II where R1 is a (poly)ethylene glycol (6) group terminating with a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 650 Compound 1/2 according to general formula II where R1 is a sulfonamide group -L-SO2NH—P—Z where Z is a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 650 Compound 1/2 according to general formula II where R1 is a carboxamide group -L-CONH—P—Z where Z is a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 650 Compound 1/2 according to general formula II where R2 is an ethylene glycol group terminating with a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 650 Compound 1/2 according to general formula II where R2 is a diethylene glycol group terminating with a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 650 Compound 1/2 according to general formula II where R2 is a (poly)ethylene glycol (3) group terminating with a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 650 Compound 1/2 according to general formula II where R2 is a (poly)ethylene glycol (4) group terminating with a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 650 Compound 1/2 according to general formula II where R2 is a (poly)ethylene glycol (5) group terminating with a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 650 Compound 1/2 according to general formula II where R2 is a (poly)ethylene glycol (6) group terminating with a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 650 Compound 1/2 according to general formula II where R2 is a sulfonamide group -L-SO2NH—P—Z where Z is a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 650 Compound 1/2 according to general formula II where R2 is a carboxamide group -L-CONH—P—Z where Z is a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 650 Compound 1/3 according to general formula II where both R1 and R2 are an ethylene glycol group terminating with a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 650 Compound 1/3 according to general formula II where both R1 and R2 are a diethylene glycol group terminating with a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 650 Compound 1/3 according to general formula II where both R1 and R2 are a (poly)ethylene glycol (3) group terminating with a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 650 Compound 1/3 according to general formula II where both R1 and R2 are a (poly)ethylene glycol (4) group terminating with a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 650 Compound 4/4 according to general formula III where both R1 and R2 are a (poly)ethylene glycol (4) group terminating with a methyl group, and R7 and R8 are sulfo, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 650 Compound 4/4 according to general formula III where both R1 and R2 are a (poly)ethylene glycol (4) group terminating with a methyl group, and R7 and R8 are H, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 650 Compound 1/3 according to general formula II where both R1 and R2 are a (poly)ethylene glycol (5) group terminating with a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 650 Compound 1/3 according to general formula II where both R1 and R2 are a (poly)ethylene glycol (6) group terminating with a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 650 Compound 1/3 according to general formula II where both R1 and R2 are a sulfonamide group -L-SO2NH—P—Z where Z is a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 650 Compound 1/3 according to general formula II where both R1 and R2 are a carboxamide group -L-CONH—P—Z where Z is a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 650 Compound 1/2 according to general formula II where R8 is an ethylene glycol group terminating with a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 650 Compound 1/2 according to general formula II where R8 is sulfonamide —SO2NH—P—Z where Z is a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 650 Compound 1/2 according to general formula II where R8 is carboxamide —CONH—P—Z where Z is a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 650 Compound 1/2 according to general formula II where R7 is an ethylene glycol group terminating with a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 650 Compound 1/2 according to general formula II where R7 is a sulfonamide group —SO2NH—P—Z where Z is a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 650 Compound 1/2 according to general formula II where R7 is a carboxamide group —CONH—P—Z where Z is a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 650 Compound 1/3 according to general formula II where both R7 and R8 are an ethylene glycol group terminating with a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 650 Compound 1/3 according to general formula II where both R7 and R8 are a sulfonamide group —SO2NH—P—Z where Z is a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 650 Compound 1/3 according to general formula II where both R7 and R8 are a carboxamide group —CONH—P—Z where Z is a methyl group, shown below:
One non-limiting example of a NHS-ester of 755 Compound 1/3, according to general formula III, where m=1 and p=1, is shown below:
One non-limiting example of a NHS-ester of 755 Compound 1/3, according to general formula III, where m=1 and p=2, is shown below:
One non-limiting example of a NHS-ester of 755 Compound 1/3, according to general formula III, where m=1 and p=3, is shown below:
One non-limiting example of a NHS-ester of 755 Compound 1/3, according to general formula III, where m=1 and p=4, is shown below:
One non-limiting example of a NHS-ester of 755 Compound 1/3, according to general formula III, where m=1 and p=5, is shown below:
One non-limiting example of a NHS-ester of 755 Compound 1/3, according to general formula III, where m=1 and p=6, is shown below:
One non-limiting example of a NHS-ester of 755 Compound 2/3, according to general formula III, where m=2 and p=1, is shown below:
One non-limiting example of a NHS-ester of 755 Compound 2/3, according to general formula III, where m=2 and p=2, is shown below:
One non-limiting example of a NHS-ester of 755 Compound 2/3, according to general formula III, where m=2 and p=3, is shown below:
One non-limiting example of a NHS-ester of 755 Compound 3/3, according to general formula III, where m=3 and p=1, is shown below:
One non-limiting example of a NHS-ester of 755 Compound 3/3, according to general formula III, where m=3 and p=2, is shown below:
One non-limiting example of a NHS-ester of 755 Compound 3/3, according to general formula III, where m=3 and p=3, is shown below:
One non-limiting example of a NHS-ester of 755 Compound 4/3, according to general formula III, where m=4 and p=1, is shown below:
One non-limiting example of a NHS-ester of 755 Compound 5/3, according to general formula III, where m=5 and p=1, is shown below:
One non-limiting example of a NHS-ester of 755 Compound 6/3, according to general formula III, where m=6 and p=1, is shown below:
One non-limiting example of an activated 755 Compound 1/2 is a tetrafluorophenyl (TFP)-ester form of 755 Compound 1/2, shown below:
One non-limiting example of an activated 755 Compound 1/2 is a sulfotetrafluorophenyl (STP)-ester form of 755 Compound 1/2, shown below:
One non-limiting example of an activated 755 Compound 1/2 is a hydrazide form of 755 Compound 1/2, shown below:
general formula VIb with “b” indicating an ethylene glycol, diethylene glycol, or (poly)ethylene glycol group on the left indole N, and the chain on the right indole N terminating in COH:
general formula VIc with “c” indicating an ethylene glycol, diethylene glycol, or (poly)ethylene glycol group on the left and right indole N, and the chain on the right indole N terminating in COX:
or general formula VId with “d” indicating an ethylene glycol, diethylene glycol, or (poly)ethylene glycol group on the left and right indole N, and the chain on the right indole N terminating in COH:
where each of R1, R2, R5, and R6 is the same or different and is independently selected from the group consisting of an aliphatic, heteroaliphatic, sulfoalkyl group, heteroaliphatic with terminal SO3, a PEG group P-L-Z where P is selected from an ethylene glycol group, a diethylene glycol group, and a (poly)ethylene glycol group, where the (poly)ethylene glycol group is (CH2CH2O)s, where s is an integer from 3-6 inclusive, a sulfonamide group -L-SO2NH—P-L-Z, and a carboxamide group -L-CONH—P-L-Z; each of R7 and R8 is the same or different and is independently selected from either H, SO3, a PEG group P-L-Z where P is selected from an ethylene glycol group, a diethylene glycol group, and a (poly)ethylene glycol group, where the (poly)ethylene glycol group is (CH2CH2O)s, where s is an integer from 3-6 inclusive, a sulfonamide group —SO2NH—P-L-Z, or a carboxamide group —CONH—P-L-Z; where L is selected from the group consisting of a divalent linear (—(CH2)o—, o=0 to 15), crossed, or cyclic alkane group that can be substituted by at least one atom selected from the group consisting of oxygen, substituted nitrogen, and/or sulfur; where Z is selected from the group consisting of H, CH3, alkyl, a heteroalkyl group, NH2, —COO−, —COOH, —COSH, CO—NH—NH2, —COF, —COCl, —COBr, —COI, —COO-Su (succinimidyl/sulfosuccinimidyl), —COO-STP (4-sulfo-2,3,5,6-tetrafluorophenyl), —COO-TFP (2,3,5,6-tetrafluorophenyl), —COO-benzotriazole, —CO-benzotriazole, —CONR′—CO—CH2—I, —CONR′R″, —CONR′-biomolecule, —CONR′-L-COO−, —CONR′-L-COOH, —CONR′-L-COO-Su, —CONR′-L-COO-STP, —CONR′-L-COO-TFP, —CONR′-L-CONR″2, —CONR′-L-CO-biomolecule, —CONR′-L-CO—NH—NH2, —CONR′-L-OH, —CONR′-L-O-phosphoramidite, —CONR′-L-CHO, —CONR′-L-maleimide, and —CONR′-L-NH—CO—CH2—I; R′ and R″ is selected from the group consisting of H, aliphatic group, and heteroaliphatic group, and the biomolecule is a protein, antibody, nucleotide, oligonucleotide, biotin, or hapten; X is selected from the group consisting of —OH, —SH, —NH2, —NH—NH2, —F, —Cl, —Br, I, —NHS (hydroxysuccinimidyl/sulfosuccinimidyl), —O-TFP (2,3,5,6-tetrafluorophenoxy), —O-STP (4-sulfo-2,3,5,6-tetrafluorophenoxy), —O-benzotriazole, -benzotriazole, —NR-L-OH, —NR-L-O-phosphoramidite, —NR-L-SH, —NR-L-NH2, —NR-L-NH—NH2, —NR-L-CO2H, —NR-L-CO—NHS, —NR-L-CO-STP, —NR-L-CO-TFP, —NR-L-CO-benzotriazole, —NR-L-CHO, —NR-L-maleimide, and —NR-L-NH—CO—CH2-I, where R is —H or an aliphatic or heteroaliphatic group; Kat is a number of Na+, K+, Ca2+, ammonia, or other cation(s) needed to compensate the negative charge brought by the cyanine; m is an integer from 0 to 5 inclusive; p is an integer from 1 to 6 inclusive; each of R3 and R4 is the same or different and is independently hydrogen, an aliphatic group, a heteroaliphatic group, or a PEG group P-L-Z where P is selected from an ethylene glycol group, a diethylene glycol group, and a (poly)ethylene glycol group, where the (poly)ethylene glycol group is (CH2CH2O)s, where s is an integer from 3-6 inclusive; or R3 and R4 together form a cyclic structure where R3 and R4 are joined using a divalent structural element selected from the group consisting of —(CH2)q—, —(CH2)qO(CH2)q′—, —(CH2)qS(CH2)q′—, —(CH2)qCH═CH—, —OCH═CH— where each of q and q′ is the same or different and is a integer from 2 to 6 inclusive; and Y is selected from the group consisting of hydrogen, alkyl, sulfoalkyl, fluorine, chlorine, bromine, a PEG group P-L-Z where P is selected from an ethylene glycol group, a diethylene glycol group, and a (poly)ethylene glycol group, where the (poly)ethylene glycol group is (CH2CH2O)s, where s is an integer from 3-6 inclusive, and an oxygen-containing group ORPM where RPM is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cyclic alkyl, substituted or unsubstituted heterocyclic alkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, where the group can be substituted with at least one of hydroxyl, sulfo, carboxy, and/or amino; with the proviso that at least one of R1, R2, R3, R4, R5, R6, R7, and R8 contains a PEG group.
One non-limiting example of an additionally PEG-substituted compound is a 755 Compound 1/2 according to general formula II where R1 is a diethylene glycol group terminating with a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 755 Compound 1/2 according to general formula II where R1 is a (poly)ethylene glycol (3) group terminating with a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 755 Compound 1/2 according to general formula II where R1 is a (poly)ethylene glycol (4) group terminating with a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 755 Compound 1/2 according to general formula II where R1 is a (poly)ethylene glycol (5) group terminating with a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 755 Compound 1/2 according to general formula II where R1 is a (poly)ethylene glycol (6) group terminating with a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 755 Compound 1/2 according to general formula II where R1 is a sulfonamide group -L-SO2NH—P—Z where Z is a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 755 Compound 1/2 according to general formula II where R1 is a carboxamide group -L-CONH—P—Z where Z is a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 755 Compound 1/2 according to general formula II where R2 is an ethylene glycol group terminating with a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 755 Compound 1/2 according to general formula II where R2 is a diethylene glycol group terminating with a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 755 Compound 1/2 according to general formula II where R2 is a (poly)ethylene glycol (3) group terminating with a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 755 Compound 1/2 according to general formula II where R2 is a (poly)ethylene glycol (4) group terminating with a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 755 Compound 1/2 according to general formula II where R2 is a (poly)ethylene glycol (5) group terminating with a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 755 Compound 1/2 according to general formula II where R2 is a (poly)ethylene glycol (6) group terminating with a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 755 Compound 1/2 according to general formula II where R2 is a sulfonamide group -L-SO2NH—P—Z where Z is a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 755 Compound 1/2 according to general formula II where R2 is a carboxamide group -L-CONH—P—Z where Z is a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 755 Compound 1/3 according to general formula II where both R1 and R2 are an ethylene glycol group terminating with a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 755 Compound 1/3 according to general formula II where both R1 and R2 are a diethylene glycol group terminating with a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 755 Compound 1/3 according to general formula II where both R1 and R2 are a (poly)ethylene glycol (3) group terminating with a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 755 Compound 1/3 according to general formula II where both R1 and R2 are a (poly)ethylene glycol (4) group terminating with a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 755 Compound 4/4 according to general formula II where both R1 and R2 are a (poly)ethylene glycol (4) group terminating with a methyl group, and R7 and R8 are sulfo, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 755 Compound 4/4 according to general formula II where both R1 and R2 are a (poly)ethylene glycol (4) group terminating with a methyl group, and R7 and R8 are H, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 755 Compound 1/3 according to general formula II where both R1 and R2 are a (poly)ethylene glycol (5) group terminating with a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 755 Compound 1/3 according to general formula II where both R1 and R2 are a (poly)ethylene glycol (6) group terminating with a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 755 Compound 1/3 according to general formula II where both R1 and R2 are a sulfonamide group -L-SO2NH—P—Z where Z is a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 755 Compound 1/3 according to general formula II where both R1 and R2 are a carboxamide group -L-CONH—P—Z where Z is a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 755 Compound 1/2 according to general formula II where R8 is an ethylene glycol group terminating with a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 755 Compound 1/2 according to general formula II where R8 is sulfonamide —SO2NH—P—Z where Z is a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 755 Compound 1/2 according to general formula II where R8 is carboxamide —CONH—P—Z where Z is a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 755 Compound 1/2 according to general formula II where R7 is an ethylene glycol group terminating with a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 755 Compound 1/2 according to general formula II where R7 is a sulfonamide group —SO2NH—P—Z where Z is a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 755 Compound 1/2 according to general formula II where R7 is a carboxamide group —CONH—P—Z where Z is a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 755 Compound 1/3 according to general formula II where both R7 and R8 are an ethylene glycol group terminating with a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 755 Compound 1/3 according to general formula II where both R7 and R8 are a sulfonamide group —SO2NH—P—Z where Z is a methyl group, shown below:
One non-limiting example of an additionally PEG-substituted compound is a 755 Compound 1/3 according to general formula II where both R7 and R8 are a carboxamide group —CONH—P—Z where Z is a methyl group, shown below:
Synthesis of numerous modifications of the core indocyanine structure have been described. Such modifications provided various functionalities, e.g., synthesis of N-isothiocyanato-alkyl- and aromatic-carboxyalkyl-functionalized indocyanines were described in U.S. Pat. Nos. 5,627,027; 6,048,982; 4,981,977; U.S. Publication No. 2006/0199949; Southwick, Anal. Chem. 67 (1995) 1742-48).
Synthesis of indocyanines with one or two N-carboxyalkyl functionalities were described in U.S. Pat. Nos. 5,268,486; 5,486,616; 5,569,587; 5,569,766; JP 03217837.
Synthesis of indocyanines containing C-carboxyalkyl groups were described in JP 05-313304; U.S. Publication Nos. 2006/0099638, 2006/0004188; 2002/0077487; 2002/0064794; U.S. Pat. Nos. 6,977,305 and 6,974,873.
Synthesis of indocyanines with N- and C-sulfoalkyl groups were described in JP 05-313304; WO 2005/044923; U.S. Publication No. 2007/0203343.
Synthesis of indocyanines with mixed C-carboxyalkyl and C-sulfoalkyl were described in EP 1792949 and U.S. Pat. No. 7,745,640.
Synthesis of indocyanines having a PEG-containing, N-carboxyalkyl spacer were described in U.S. Pat. No. 6,939,532.
Functionalization of the N-carboxyalkyl with an amino-functionalized PEG-alkyl chain, and N- and C-substituted PEG-alkyl chains, were described in U.S. Publication No. 2009/0305410.
Synthesis of various polymethine bridge substitutions, and other functionalizations of indocyanines, were described in Strekowski, Heterocyclic Polymethine Dyes: Synthesis, Properties and Applications, (2008) Springer-Verlag, Berlin Heidelberg; Gragg, “Synthesis of Near-Infrared Heptamethine Cyanine Dyes” (2010). Chemistry Theses. Paper 28. http://digitalarchive.gsu.edu/chemistry_theses/28; Patonay et al. (2004) Noncovalent Labeling of Biomolecules with Red and Near-Infrared Dyes, Molecules 9 (2004) 40-49; and U.S. Pat. No. 7,172,907.
Six hundred and sixteen mg (1 mmol) 1-(5-Carboxypentyl)-3-methyl-2-((1E,3E,5E)-6-phenylamino-hexa-1,3,5-trienyl)-5-sulfo-3-(3-sulfopropyl)-3H-indolium and 404 mg (1 mmol) 1-(2-methoxy-ethyl)-2,3-dimethyl-5-sulfo-3-(3-sulfopropyl)-3H-indolium were dissolved in 20 ml of acetic acid/acetic anhydride (1/1) followed by the addition of 200 mg of sodium acetate. The solution was stirred under reflux for 15 min. After cooling to room temperature, 20 ml diethylether was added. The resulting precipitate (mixture of the diastereomers 755 Compound 1 (isomer 1) and 755 Compound 1 (isomer 2)) was extracted by suction, washed with ether, and dried.
Both 1 mmol 1-(5-Carboxypentyl)-3-methyl-2-((1E,3E,5E)-6-phenylamino-hexa-1,3,5-trienyl)-5-sulfo-3-(3-sulfopropyl)-3H-indolium and 1 mmol 1-[2-(2-methoxy-ethoxy)-ethyl]-2,3-dimethyl-5-sulfo-3-(3-sulfo-propyl)-3H-indolium were dissolved in 20 ml acetic acid/acetic anhydride (1/1) followed by the addition of 200 mg sodium acetate. The solution was stirred under reflux for 15 min. After cooling to room temperature, 20 ml diethylether was added. The resulting precipitate (mixture of the diastereomers 755 compound 2 (isomer 1) and 755 compound 2 (isomer 2)) was extracted by suction, washed with ether and dried. The residue is purified by column chromatography (RP-18, acetonitrile/water and concentrated HCl), thereby separating the diastereomers from each other, as described in Example 16.
Both 1 mmol 1-(5-carboxypentyl)-3-methyl-2-((1E,3E,5E)-6-phenylamino-hexa-1,3,5-trienyl)-5-sulfo-3-(3-sulfopropyl)-3H-indolium and 1 mmol 1-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl}-2,3-dimethyl-5-sulfo-3-(3-sulfo-propyl)-3H-indolium were dissolved in 20 ml acetic acid/acetic anhydride (1/1) followed by the addition of 200 mg sodium acetate. The solution was stirred under reflux for 15 min. After cooling to room temperature, 20 ml diethylether was added. The resulting precipitate (mixture of the diastereomers 755 compound 3 (isomer 1) and 755 compound 3 (isomer 2)) was extracted by suction, washed with ether and dried. The residue is purified by column chromatography (RP-18, acetonitrile/water and concentrated HCl), thereby separating the diastereomers from each other, as described in Example 16.
650 1/1- |
650 1/1-NHS | Alexa Fluor | CF 647- | ||
(tetrasulfonated) | 650 4/4-NHS | (disulfonated) | 647-NHS | NHS | |
MW (g/mol) | 1066 | 1424.63 | 789.91 | ~1150 | 3241 |
Ex (nm) | 652 | 658 | 651 | 650 | 650 |
Em (nm) | 672 | 681 | 665 | 665 | 665 |
ε (M−1cm−1) | 250,000 | 250,000 | 250,000 | 239,000 | 240,000 |
(theoretical) | |||||
|
1/1 | 4/4 | 1/1 | N/A | unknown |
(length/# of | |||||
chain) | |||||
|
4 | 2 | 2 | unknown | |
DyLight 800-NHS | 755 |
|
MW (g/mol) | 1050 | 1684.9 |
Ex (nm) | 777 | 783 |
Em (nm) | 794 | 797 |
ε (M−1cm−1) | 270,000 | 270,000 |
(theoretical) | ||
PEG | N/ |
4/4 |
(length/number of | ||
PEG groups on | ||
| ||
Sulfonates | ||
3 | 3 | |
GAM | 2.5X | | 10X | 15X | |||
650 |
2.4 | 4.7 | 9.6 | 14.2 | |
650 |
2.6 | 4.4 | 7.9 | 10.0 | |
CF 647-NHS | 1.7 | 2.9 | 4.3 | 5.1 | |
Alexa Fluor 647-NHS | 2.4 | 4.0 | 6.5 | 8.2 | |
GAR | 2.5X | | 10X | 15X | |||
650 | 2.3 | 4.6 | 8.5 | 13.4 | |
650 | 2.8 | 4.1 | 7.6 | 10.0 | |
CF 647-NHS | 1.7 | 2.6 | 4.2 | 4.9 | |
Alexa Fluor 647-NHS | 2.3 | 3.6 | 6.1 | 7.7 | |
Labeling efficiency was the highest for all 650
2.5X | 5X | 7X | 9X | |
GAM borate buffer | |||||
755 |
0.97 | 1.72 | 2.24 | 2.94 | |
DyLight 800-NHS | 0.74 | 1.12 | 1.41 | 1.91 | |
GAR borate buffer | |||||
755 |
0.84 | 1.64 | 2.22 | 2.91 | |
DyLight 800-NHS | 0.71 | 1.17 | 1.39 | 1.88 | |
GAM borate buffer | |||||
755 |
1.75 | 2.32 | |||
DyLight 800-NHS | 1.20 | 1.55 | |||
GAM PBS buffer | |||||
755 |
0.74 | 1.16 | |||
DyLight 800-NHS | 0.89 | 1.15 | |||
755 |
pH | LogD | |
1.50 | −1.43 | |
5.00 | −1.77 | |
6.50 | −1.77 | |
7.40 | −1.77 | |
LogP ionic species = −1.8 | ||
LogP nonionic species = 1.0 (3.2 considering tautomerization/resonance) | ||
LogD at pl = 0.2 (2.4 considering tautomerization/resonance) |
|
pH | LogD | |
1.50 | 1.44 (1.42 considering tautomerization/resonance) | |
5.00 | −0.31 | |
6.50 | −0.32 | |
7.40 | −0.32 | |
LogP ionic species = −0.3 | ||
LogP nonionic species = 2.4 (4.7 considering tautomerization/resonance) | ||
LogD at pl = 2.8 (5.1 considering tautomerization/resonance) |
Claims (11)
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